Submit or Track your Manuscript LOG-IN

Advances in Animal and Veterinary Sciences

AAVS_8_4_370-384

 

 

Research Article

 

Effects of Rutin and Quercetin on Doxorubicin-Induced Renocardiotoxicity in Male Wistar Rats

 

Heba Uallah R. Mahmoud, Osama M. Ahmed, Hanaa I. Fahim, Noha A. Ahmed*, Mohamed B. Ashour

Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt.

 

Abstract | This study aims to assess the preventive effects of rutin and/or quercetin on doxorubicin-induced kidney and heart injuries and oxidative stress in male Wistar rats. The male Wistar rats, injected with doxorubicin at an intraperitoneal dose 2 mg/kg b.w. 2 days per week for 5 weeks, were orally treated with rutin and/or quercetin with dose level 50 mg /kg b.w. every other day for 5weeks. The treatments of doxorubicin-injected rats with rutin, quercetin and their combination resulted in a significant decrease in the elevated serum creatinine and urea levels reflecting an improvement in kidney function. Similarly, the elevated serum CK-MB and LDH activities were significantly ameliorated as a result of treatments of doxorubicin-injected rats, thereby manifesting an amendment of heart function. The treatments also led to the prevention of the elevated lipid peroxidation and amelioration of the lowered GPx, GST and SOD activities as well as GSH content in kidney and heart as a result of treatment of doxorubicin-injected rats with rutin and quercetin. Also, the treatments remarkably improved doxorubicin-induced deleterious histological alterations in kidney and heart. In conclusion, rutin and/or quercetin may have chemopreventive potentials against doxorubicin-induced nephrocardiotoxicity via suppression of oxidative stress and enhancement of antioxidant defense system.

 

Keywords | Rutin, Quercetin, Doxorubicin, Kidney, Heart, Oxidative stress

 

Received | December 05, 2019; Accepted | February 17, 2020; Published | March 20, 2020

*Correspondence | Noha A. Ahmed, Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Salah Salim St., 62514, Beni-Suef, Egypt. Email: drnohascience@science.bsu.edu.eg, drnohascience@gmail.com

Citation | Mahmoud HUR, Ahmed OM, Fahim HI, Ahmed NA, Ashour MB (2020). Effects of rutin and quercetin on doxorubicin-induced renocardiotoxicity in male wistar rats. Adv. Anim. Vet. Sci. 8(4): 370-384.

DOI | http://dx.doi.org/10.17582/journal.aavs/2020/8.4.370.384

ISSN (Online) | 2307-8316; ISSN (Print) | 2309-3331

Copyright © 2020 Mahmoud et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

INTRODUCTION

 

Cancer chemotherapy is considered to be a major treatment at late stages to avoid the remission of cancer after surgery (Poornima et al., 2014). It is a typical methodology of treatment for several types of cancer (Sahin et al., 2010).

 

Doxorubicin is one of the most effective anticancer chemotherapeutic belonging to anthracycline antibiotic group and it has a large spectrum of activity (Coldwell et al., 2010). It is being used alone or in combination to treat a variety of tumors, both hematological and solid, such as breast cancer (Jabłonska-Trypuc et al., 2017). Despite its therapeutic value, doxorubicin has significant cardiotoxicity (Kuznetsova et al., 2011), hepatotoxicity (Patel et al., 2010) nephrotoxicity (Mohan et al., 2010) and testicular toxicity (Trivedi et al., 2011) which limit its clinical application. It also inhibits cell proliferation, induces oxidative stress, inhibits topoisomerase II, and finally leads to the cell death mainly through apoptosis (Ta et al., 2008; Sathesh et al., 2010; Cao et al., 2013). Although inflammation, apoptosis, mitochondrial DNA damage, impairment of calcium metabolism and excessive production of free radicals may all contribute to a variable extent to the deterioration of organ function, the exact mechanism of doxorubicin-mediated multiple organ toxicity remains largely unknown (Gharanei et al., 2014). Doxorubicin tends to accumulate in mitochondria, causing changes in their structure and function. However, the main cause of doxorubicin side effects observed in human and experimental animals is an extremely high level of oxidative stress within the cell, eventually causing apoptotic cell death (Hozayen et al., 2013; Taskin and Dursun, 2015; Yapislar et al., 2016).

 

Reactive oxygen species (ROS) are extremely harmful to organisms at high concentrations. Once the amount of ROS exceeds the defense mechanisms, a cell is claimed to be during a state of “oxidative stress”. The increased production of ROS throughout environmental stresses will cause a threat to cells by inflicting peroxidation of lipids, oxidization of proteins, harm to nucleic acids, enzymes inhibition, activation of programmed cell death (PCD) pathway and ultimately resulting in death of the cells (Mishra et al., 2011; Srivastava and Dubey, 2011; Mesquita and Leão, 2018). It was reported that oxidative stress may be implicated in doxorubicin-induced toxicity of different body organs including kidney and heart (Ahmed et al., 2017; Songbo et al., 2019; Ahmed et al., 2019). Thus, the use of antioxidant agents such as flavonoids in combination with doxorubicin may reduce or inhibits the doxorubicin-induced side effects.

 

Flavonoids and the other phenolic compounds are commonly known as plant secondary metabolites that hold an aromatic ring bearing at least one hydroxyl groups. More than 8000 phenolic compounds as naturally occurring substances from plants have been reported (Kumar and Pandey, 2013a; Ahmed et al., 2016). It is very interesting to note that half of these phenolic compounds are flavonoids presenting as aglycone, glycosides and methylated derivatives (Kumar and Pandey, 2013b). These phytochemical substances are presented in nutrients and herbal medicines, both flavonoids and many other phenolic components have been reported on their effective antioxidant, anticancer, antibacterial, cardioprotective, anti-inflammatory, immune system promoting and skin protective properties (Działo et al., 2016; Andreu et al., 2018; Meng et al., 2018).

 

Rutin (quercetin rutinoside) is considered to be a glycoside of the flavonoid quercetin. Rutin is used as a drug for protection of blood vessel and is an ingredient of various multivitamin preparations and herbal remedies. It can combine with cations, supplying nutrients from the soil to the cells in plants (Luo et al., 2008). In humans, it is a potent antioxidant where its actions include attaching to the iron ion Fe+2, preventing it from binding to hydrogen peroxide, which would otherwise create a highly-reactive free-radical that may damage cells (Patel et al., 2010). Rutin also shows anti-inflammatory activities in some animal and in vitro models (Guardia et al., 2001).

 

Quercetin may be a plant-derived aglycone form of flavonoid glycosides, has been used as a nutritionary supplement and should be useful against a lot of diseases. Some of the beneficial effects include cardiovascular protection, anticancer, antitumor, anti-ulcer, anti-allergy, anti-viral, anti-inflammatory, anti-diabetic, gastroprotective, antihypertensive, immunomodulatory and anti-infective properties (Lakhanpal and Rai, 2007). Epidemiological survey showed diet with more vegetables and fruits have protective effect against cancer. Quercetin has potential anticancer properties which include antiproliferative, growth factor suppression and antioxidant (Lamson and Brignall, 2000).

 

Therefore, this current study was conducted to assess the preventive and antioxidant effects of rutin and quercetin and their combination on doxorubicin-induced kidney and heart injuries in male Wistar rats.

 

MATERIALS AND METHODS

 

Experimental animals and housing

Fifty male Wistar rats weighing about 120-140 g (9-10 weeks old), were used as experimental animals in the present investigation. They were obtained from the Animal House of the National Research Center, Dokki, Giza, Egypt. Animals were acclimatized to laboratory conditions and under observation 10 days before the onset of the experiment to exclude any intercurrent infection. The animals were housed in polypropylene cages with good aerated stainless steel covers at normal atmospheric temperature (25±5ºC) and 12 hrs daily normal light-dark cycles. Rats were given access of water and supplied daily enough balanced standard diet ad libitum. All animal procedures are in accordance with the recommendations and guidelines of the Ethics Committee for Care and Use of Experimental Animals, Faculty of Science, Beni-Suef University, Egypt (Ethical Approval number: BSU/FS/2015/22). All efforts were done to minimize the pain, distress and discomfort.

 

Chemicals and drugs

The doxorubicin in the form adriamycin hydrochloride was obtained from Pharmacia Italia (Milan, Italy). Rutin and quercetin were obtained from Sigma Chemical Company (St. Louis, MO, USA). All other chemicals used for the investigation were ultra-pure and were commercially obtained.

 

Doses and treatment

The animals were treated with doxorubicin by an intraperitoneal route. The chosen dose was adjusted to 2 mg/1ml saline (0.9% NaCl)/kg b.w. (Mandziuk et al., 2015) and was given 2 times per week for five weeks. Rutin and quercetin doses were adjusted to 50 mg/kg b.w (Suganya and Sumathi, 2016; Bo et al., 2018) and were orally given every other day for five weeks by oral gavage for five weeks. They were dissolved in 1% carboxymethyl cellulose (1% CMC) at concentration 50 mg rutin or quercetin/5 ml 1% CMC.

 

Animal grouping

The adult male Wistar rats used in the present experiment were divided into five groups (10 rats for each).

 

Group 1 (Normal group): Rats of this group were intraperitoneally injected with the equivalent volume of saline (1 ml/kg b.w.) every other day for five weeks. This group was also orally administered the equivalent volume of 1% CMC (5 ml/kg b.w.) every other day for five weeks.

 

Group 2 (Doxorubicin-injected control group): Rats of this group were intraperitoneally injected with doxorubicin at dose level 2 mg/kg b.w. (Mandziuk et al., 2015) 2 days per week for five weeks. This group was also orally administered the equivalent volume of 1% CMC (5 ml/kg b.w.) every other day for five weeks.

 

Group 3 (Doxorubicin-injected group treated with rutin): This group was intraperitoneally injected with doxorubicin like doxorubicin-injected control group and was orally treated (by oral gavage) with rutin at dose level of 50 mg /kg b.w. (Suganya and Sumathi, 2016) every other day for five weeks.

 

Group 4 (Doxorubicin-injected group treated with quercetin): Rats of this group were intraperitoneally injected with doxorubicin like doxorubicin-injected control group and were also orally treated with quercetin at dose level 50 mg/kg b.w. (Bo et al., 2018) every other day for five weeks.

 

Group 5 (Doxorubicin-injected group treated with rutin and quercetin): Rats of this group were intraperitoneally injected with doxorubicin like doxorubicin-injected control group and were also orally treated with mixture of rutin and quercetin at dose level 50 mg/kg b.w. every other day for five weeks.

 

Blood and tissue sampling

At the end of the experiment, rats were anesthetized by a diethyl ether inhalation anesthesia and blood sample from each rat was collected from jugular vein into centrifuge tube. The blood samples were left to clot at room temperature for 45 minutes and then centrifuged at 3000 r.p.m. for 15 minutes. The clear, non-heamolysed supernatant sera were quickly removed, divided into four portions for each individual animal and kept at -30ºC for various biochemical analyses. After sacrifice and dissection, one kidney and half of heart were removed quickly, separately homogenized by using Telfon homogenizer (Glas-Col, Terre Haute, USA), in isotonic solution (0.9% NaCl) at 10% concentration (w/v). The resultant homogenates were centrifuged at 3000 r.p.m. and the homogenate supernatants were aspirated and divided into three portions, and then kept in deep freezer at -30oC till used for determination of oxidative stress and antioxidant defense markers.

 

Biochemical investigations

Serum creatinine and urea levels were determined by kinetic method using kits obtained from Diamond Diagnostics (Egypt) according to Young (2001). CK-MB activity in serum was determined according to method of Young (1995) using reagent kits purchased from Spinreact (Spain). LDH activity in serum was determined according to method of Young (1990) using reagent kits purchased from Spectrum, Egypt. Kidney and heart malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) levels were determined according to the methods of Preuss et al. (1998), Beutler et al. (1963), Matkovics et al. (1998), Mannervik and Gutenberg (1981), and Marklund and Marklund (1974), respectively.

 

Histopathological investigations

For histopathological examination, one half of kidney and half of heart from each animal were fixed in 10% neutral buffered formalin and transferred to the Pathology Department, National Cancer Institute, Cairo university, Egypt for processing, sectioning and staining with hematoxylin and eosin (H and E) according to the method of Banchroft et al. (1996).

 

Statistical analysis

Results were expressed as mean ± standard error (SE). One-way ANOVA followed by LSD test were applied for data analysis using PC-STAT program (Rao et al., 1985). F-probability of ANOVA results expresses the general effect between groups at p<0.05, p<0.01 and p<0.001. For each parameter, LSD test was used to compare various groups with each other’s at p<0.05 and p<0.01.

 

RESULTS

 

Biochemical effects

The data describing the effect of rutin and/or quercetin on serum creatinine and urea levels in doxorubicin-administered rats are represented in Table 1. Serum creatinine and urea levels exhibited a highly significant elevation (p<0.01; LSD) in doxorubicin-injected control rats; the recorded percentage changes were 21.05% and 82.99% respectively as compared to normal control. The treatment of doxorubicin-injected rats with rutin and/or quercetin produced a highly significant decrease (p<0.01; LSD) in serum creatinine and urea levels. Quercetin was the most potent in decreasing the elevated creatinine and urea levels recording percentage decreases of 33.33% and 46.32% respectively (Table 1).

 

The data elucidating the effect of rutin and/or quercetin on serum CK-MB and LDH activities are represented in Table 2. Doxorubicin injection induced a significant increase (p<0.05; LSD) and a highly significant increase (p<0.01; LSD) in serum CK-MB and LDH activities recording percentage changes 19.29% and 33.20% respectively. On the other hand, the administration of rutin, quercetin and their combination to doxorubicin-injected rats produced a highly significant decrease (p<0.01; LSD) in serum CK-MB and LDH activities. It seemed that quercetin was the most potent in decreasing the elevated CK-MB and LDH activities recording percentages decreases of 27.60% and 35.63% respectively.

 

The data depicting the effect of rutin and/or quercetin on GSH content in kidney and heart are represented in Table 3. In the kidney, the treatment with quercetin produced a highly significant increase (P<0.01; LSD) recording percentage change of 48.25% while the treatment with rutin alone and with its combination with quercetin induced a non-significant increase (LSD; P>0.05) of GSH content recording percentage changes of 24.71% and 25.29% respectively. In heart, doxorubicin-injected group treated with quercetin and combination of rutin and quercetin caused a non-significant increase of GSH content (P>0.05) recording percentage increases of 9.18% and 8.17% respectively while the treatment with rutin alone induced produced a highly significant increase (P<0.01; LSD).

 

Data showing the effect of rutin and/or quercetin on kidney and heart LPO in doxorubicin-injected rats are represented in Table 4. The administration of doxorubicin to Wistar rats caused a highly significant elevation (P<0.01; LSD) of LPO in kidney and heart; the percentage changes marked an increase of 71.60%and 64.31% respectively as compared to normal rats. The kidney LPO exhibited a highly significant decrease (P<0.01; LSD) in doxorubicin-injected rats treated with rutin, quercetin and their combination recording percentage changes of -37.96%, -36.25% and -26.50% respectively. Similarly, doxorubicin-injected rats treated with rutin, quercetin and their combination exhibited a highly significant decrease in heart LPO; rutin is considered the most effective in decreasing the elevated LPO recording percentage amelioration of 52.32%.

 

Data describing the effect of rutin and/or quercetin on serum GPx activity in doxorubicin-injected rats are represented in Table 5. The administration of doxorubicin to Wistar rats caused a non-significant effect on kidney GPx activity, but it produced a highly significant decrease (P<0.01; LSD) in heart GPx activity recording percentage change of 9.41% as compared with normal control.

 

The treatment of doxorubicin-injected rats with rutin produced a highly significant increase (P<0.01; LSD) in kidney GPx activity recording percentage change of 7.51% while the treatment with quercetin and its combination with rutin induced a non-significant effect (P>0.05; LSD). On other hand, the treatment with rutin, quercetin and their combination all have no significant effect on heart GPx activity (P>0.05; LSD) as compared with doxorubicin-injected control rats.

 

Data elucidating the effect of rutin and/or quercetin on serum of GST activities in doxorubicin-injected rats are represented in Table 6. The administration of doxorubicin to Wistar rats caused a highly significant decrease (P<0.01; LSD) kidney and heart GST activity; the recorded percentage changes were -41.05% and -34.50% respectively. The treatment doxorubicin-injected rats with rutin induced a non-significant effect (P>0.05; LSD) on heart GST activity and the recorded percentage change 15.86% and produced a highly significant increase (P<0.01; LSD) in kidney GST activity with a recorded percentage change 39.11%. On the other hand, the treatment with quercetin induced a highly significant increase (P<0.01; LSD) in kidney and heart GST activity and the recorded percentage changes were 70.23% and 49.70% respectively. The treatment with a combination of rutin and/or quercetin induced a highly significant increase (P<0.01; LSD) in kidney and heart GST activity and the recorded percentage changes were 55.13% and 57.50% respectively.

 

Data describing the effect of rutin and/or quercetin on serum of SOD activity in doxorubicin-injected rats are represented in Table 7. The administration of doxorubicin to Wistar rats caused a highly significant decrease (P<0.01; LSD) in heart SOD activity; the recorded percentage was -5.45% while it produced a non-significant effect (P>0.05; LSD) on kidney SOD activity as compared with normal control. The treatment of doxorubicin-injected rats with rutin induced a highly significant increase (P<0.01; LSD) in kidney SOD activity recording percentage change of 17.62%, but it produced a non-significant increase (P>0.05; LSD) in heart SOD activity. On the other hand, the treatment with quercetin induced a highly significant increase (P<0.01; LSD) in heart SOD activity recording percentage change of 11.24% while it caused a non-significant increase (P>0.05; LSD) in kidney SOD activity. The treatment with combination of rutin and quercetin induced a highly significant increase (P<0.01; LSD) in kidney and heart SOD activity; the recorded percentage changes were 18.67% and 16.21% respectively as compared to doxorubicin-injected control rats.

 

Table 1: Effect of rutin and quercetin on serum parameters related to kidney functions in doxorubicin-injected rats.

 

Parameter group Creatinine (mg/dL) %Change

Urea (mg/dL) %Change

Normal control

0.57± 0.01 b

 

37.16 ±1.68b

 
Doxorubicin-injected control group

0.69 ±0.01a

21.05%

68.00 ±8.62a

82.99%
Doxorubicin-injected group treated with rutin

0.56 ± 0.01b

-18.84%

47.31 ±2.48b

-30.43%
Doxorubicin-injected group treated with quercetin

0.46 ±0.02c

-33.33%

36.50 ±5.68b

-46.32%
Doxorubicin-injected group treated with rutin and quercetin

0.50 ±0.03bc

-27.53%

44.00 ±3.94b

-35.29%
F-probability

 

P< 0.001

 

P< 0.01
LSD at the 5% level

 

0.082

 

14.932
LSD at the 1% level

 

0.110

 

20.202


Data are expressed as mean± standard error. Number of detected samples in each group is six. Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

Table 2: Effect of rutin and quercetin in serum parameters related to heart functions in doxorubicin-injected rats.

 

Parameter group CK-MB ( U/L) % Change

LDH (U/L) % Change

Normal control

66.00 ±2.68b

 

1559.00 ±64.76b

 
Doxorubicin-injected control group

78.73 ±3.27a

19.29%

2076.63 ±117.54a

33.20%
Doxorubicin-injected group treated with rutin

65.50 ±1.67b

-16.80%

1446.75 ±30.27bc

-30.33%
Doxorubicin-injected group treated with quercetin

57.00 ±3.87b

-27.60%

1336.63 ±33.25c

-35.63%
Doxorubicin-injected group treated with rutin and quercetin

57.50 ±4.09b

-26.96%

1500.12 ±32.69bc

-27.76%
F-probability

 

P<0.001 P<0.001
LSD at the 5% level

 

9.435 189.254
LSD at the 1% level

 

12.765 256.045

 

Data are expressed as mean± standard error. Number of detected samples in each group is six. Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

Table 3: Effect of rutin and quercetin on kidney and heart GSH contents in doxorubicin-injected rats.

 

Parameter group Kidney GSH (nmole/100 mg tissue) % Change Heart GSH (nmole/100 mg tissue) %

Change

Normal control

117.30 ± 7.25a

 

73.98 ±3.25a

 
Doxorubicin-injected control group

64.98 ± 5.52c

-44.60%

56.54 ±2.01b

-23.57%
Doxorubicin-injected group treated with rutin

81.04 ±5.09bc

24.71%

71.66 ±2.93a

26.73%
Doxorubicin-injected group treated with quercetin

96.34 ± 4.27b

48.25%

61.73 ±2.04b

9.18%
Doxorubicin-injected group treated with rutin and quercetin

81.42 ±7.57bc

25.29%

61.17 ±2.51b

8.17%
F-probability

 

P<0.001

 

P<0.001
LSD at the 5% level

 

17.702

 

7.572
LSD at the 1% level

 

23.949

 

10.245

 

Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

Histological effects

Histological changes in kidney of normal control, doxorubicin-injected rats, doxorubicin-injected rats treated with rutin, quercetin and their combination were depicted in Figures 1a to 5d. Control group given 10% vehicle showed normal kidney architecture (Figure 1a, 1b) comprised of normal structure of glomerulus, proximal convoluted tubules, with their brush border and distal convoluted tubules.

 

On the other hand, the kidney of doxorubicin-injected rats exhibited marked changes like dilation and congestion of renal blood vessel (Figure 2a), vacuolation of endothelial lining glomerular tuft and perivascular oedema (Figure 2b) and showed peritubular mononuclear inflammatory cells infiltration (Figure 2c). Kidney sections of doxorubicin-administered rats treated with rutin showed focal mononuclear inflammatory cells infilteration (Figure 3a) and showed no hisopathological changes (Figure 3b and 3c).

 

Table 4: Effect of rutin and quercetin on kidney and heart LPO in doxorubicin-administered rats.

 

Parameter group Kidney LPO (nmole MDA/ 100 mg tissue/ hr) % Change Heart LPO (nmole MDA/100 mg tissue/ hr) % Change
Normal control

17.36 ±1.52c

 

15.97 ±1.06bc

 
Doxorubicin-injected control group

29.79 ±0.94a

71.60%

26.24 ±1.60a

64.31%
Doxorubicin-injected group treated with rutin

18.48 ±0.48bc

-37.96%

12.51 ±1.58c

-52.32%
Doxorubicin-injected group treated with quercetin

18.99 ±0.35bc

-36.25%

18.86 ±0.62b

-28.12%
Doxorubicin-injected group treated with rutin and quercetin

21.90 ±1.83b

-26.50%

17.38 ±0.96b

-33.76%
F-probability P<0.001 P<0.001
LSD at the 5% level 3.434 3.579
LSD at the 1% level 4.646 4.842


Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

Table 5: Effect of rutin and quercetin on kidney and heart GPx activity in doxorubicin-injected rats.

 

Parameter group Kidney GPx(mU/100 mg tissue) % Change Heart GPx (mU/100 mg tissue) % Change
Normal control

130.81 ±1.94b

 

137.99 ±1.72a

 
Doxorubicin-injected control group

133.16 ±1.26b

1.79%

125.00 ±1.30bc

-9.41%
Doxorubicin-injected group treated with rutin

143.17 ±1.87a

7.51%

127.14 ±2.27bc

1.71%
Doxorubicin-injected group treated with quercetin

134.04 ±1.61b

0.66%

122.24 ±2.61c

-2.21%
Doxorubicin-injected group treated with rutin and quercetin

135.69 ±1.84b

1.89%

131.67 ±4.18ab

5.33%
F-probability

 

P< 0.001

 

P< 0.01
LSD at the 5% level

 

5.034

 

7.620
LSD at the 1% level

 

6.810

 

10.309

Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

Table 6: Effect of rutin and quercetin on kidney and heart GST activity in doxorubicin-administered rats.

 

Parameter group Kidney GST (mU/100 mg tissue) %

Change

Heart GST (mU/100 mg tissue) % Change
Normal control

106.54 ±3.28a

 

97.20 ±2.89a

 
Doxorubicin-injected control group

62.80 ±4.39c

-41.05%

54.54 ±4.14c

-43.88%
Doxorubicin-injected group treated with rutin

87.36 ±3.37b

39.11%

71.19 ±7.08bc

30.50%
Doxorubicin-injected group treated with quercetin

106.91 ±8.92a

70.23%

81.66 ±7.27ab

49.70%
Doxorubicin-injected group treated with rutin and quercetin

97.42 ±9.02ab

55.13%

92.31 ±10.16a

69.22%
F-probability

 

P<0.001

 

P<0.01
LSD at the 5% level

 

18.550

 

19.845
LSD at the 1% level

 

25.097

 

26.848

 

Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

The treatment of doxorubicin-injected rats with quercetin produced congestion of renal intertubular blood vessels (Figure 4a), vacuolation of endothelial lining glomerular tuft (Figure 4b) and showed no hisopathological changes (Figure 4c). The treatment of doxorubicin-administered rats with a combination of rutin and quercetin exhibited more improvement of the kidney histological changes as compared with doxorubicin-injected control. It exhibited no histopathological changes (Figure 5a, 5b, and 5c) and showed congestion of renal blood vessels (Figure 5d).

 

Table 7: Effect of rutin and quercetin on kidney and heart SOD activity in doxorubicin-injected rats.

 

Parameter group Kidney SOD (mU/100 mg tissue) % Change Heart SOD (mU/100 mg tissue) % Change
Normal control

123.94 ±3.19b

 

133.32 ±2.25a

 
Doxorubicin-injected control group

117.19 ±2.84b

-5.45%

112.35 ±2.52c

-15.73%
Doxorubicin-injected group treated with rutin

137.84 ±2.97a

17.62%

119.26 ±1.52bc

6.15%
Doxorubicin-injected group treated with quercetin

124.44±4.51b

5.81%

124.98 ±3.18ab

11.24%
Doxorubicin-injected group treated with rutin and quercetin

139.07 ±6.41a

18.67%

130.56 ±6.56a

16.21%
F-probability

 

P<0.01

 

P<0.001
LSD at the 5% level

 

12.262

 

10.656
LSD at the 1% level

 

16.589

 

14.417

 

Means, which have the same superscript symbol(s), are not significant different. Percentage changes were calculated by comparing doxorubicin-injected control group with normal control and doxorubicin-injected groups treated with rutin and/or quercetin with doxorubicin-injected control group.

 

 



 



 


The histological changes in heart of normal control, doxorubicin-injected rats and doxorubicin-injected rats treated with rutin, quercetin and their combination were depicted in Figures 6a to 10b. Normal control group given the equivalent volumes of vehicles showed normal heart architecture (Figure 6a and 6b) with normal cardiac myocytes.

 

On the other hand, the heart of doxorubicin-injected rats exhibited marked changes like congestion of myocardial blood vessels (Figure 7a), vacuolation of sarcoplasm of cardiac myocytes (Figure 7b), focal necrosis of cardiac myocytes, inflammatory cells’ infiltration (Figure 7c) and intermuscular oedema and haemorrahage (Figure 7d).

 

Heart sections of doxorubicin-injected rats treated with rutin showed vacuolation of sarcoplasm of cardiac myocytes (Figure 8a) and no histopathological changes (Figure 8b). The treatment of doxorubicin-administered rats with quercetin produced no histopathological changes (Figure 9). Also, the treatment of doxorubicin-injected rats with a combination of rutin and quercetin showed no histopathological changes (Figure 10a and 10b).

 

 



DISCUSSION

 

Doxorubicin, a quinone-containing anthracycline antibiotic, is an important agent against a wide spectrum of human neoplasms. However, its toxicity limits usage in cancer chemotherapy (Lv et al., 2013; Xin et al., 2015; Ahmed et al., 2019a). In addition, resistance to chemotherapeutic agents is one of the major disadvantages of long-term anticancer treatment. Repeated doxorubicin administration leads to drug-resistant cancer cells and increased cytotoxicity (Ahmed et al., 2019a). It has been shown that free radicals are involved in doxorubicin-induced toxicities (Ferreira et al., 2017). It has been revealed that doxorubicin caused severe injury in some organs like liver, heart and kidneys (Gokcimen et al., 2007). The chemical structure of doxorubicin causes the generation of free radicals and the induction of oxidative stress that result in cellular injury (Saad et al., 2001; Karaman et al., 2006). Doxorubicin tends to accumulate in mitochondria, causing changes in their structure and function. However, the main cause of doxorubicin side effects observed in human is an extremely high level of oxidative stress within the cell, eventually causing apoptotic cell death (Taskin and Dursun, 2015; Yapislar et al., 2016). The increased production of mitochondrial ROS and reactive nitrogen species (RNS) induced by doxorubicin leads to an excessive oxidative stress and is strongly linked to cell damage involving reduced protein synthesis and redox modifications of macromolecules (proteins, lipids, and DNA) such as nitrotyrosine formation, protein carbonylation, and LPO which increase in doxorubicin-exposed cardiac muscle and include cellular membrane damage (Cappetta et al., 2017).

 

Doxorubicin may undergo a one-electron reduction through a metabolic activation by nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase. This reduction leads to the formation of the free radical semiquinone, which in turn can produce a variety of active ROS/RNS, including hydrogen peroxide (H2O2), hydroxyl radical (•OH) and peroxynitrite (ONOO) (Takemura and Fujiwara, 2007; Ahmed, 2013). These species can attack the cell membrane, damage several macromolecular cellular components, cause protein and LPO and consequently lead to apoptosis or death (Shiromwar and Chidrawar, 2011; Ayla et al., 2011). Doxorubicin cytotoxicity and genotoxicity may be mediated by free radicals derived from this drug and its capability to induce apoptosis through a wide variety of mechanisms including production of ROS, alkylation of cellular macromolecules, DNA intercalation and cross-linking, LPO, cell membrane damage, ceramide production and p53 induction in various tissues (Quiles et al., 2002; Lorenzo et al., 2002). Studies have proposed that oxidative stress, inflammation, and apoptosis are the main players that control doxorubicin pathogenesis (Liu et al., 2016).

 

The former approach of modulating the drug dosage was put forward, aiming to diminish the significant effects of oxidative stress, which is the major cause of cardiotoxicity, but subsequent studies revealed that minimizing or eliminating ROS did not solve the detrimental effects (Chio and Tuveson, 2017).

 

The present study revealed the effect of intraperitoneal injection of doxorubicin at dose level of 2 mg/kg b. w. 2 days/week, for 5 weeks on kidney and heart. Rutin and quercetin and their combination were given at dose level of 50 mg/kg b. w. were orally co-administered every other day to rats injected with doxorubicin to assess whether rutin or quercetin can prevent the side effects of doxorubicin on kidney and heart or not. The current results are in accordance with Injac et al. (2008), Abou Seif (2012), El-Moselhy and ElSheikh (2014) and Jacevic et al. (2018) who stated that doxorubicin-induced nephrotoxicity may be due to the finding that doxorubicin administration increased capillary permeability and glomerular atrophy. This attribution was supported by the histological findings of the present study that indicated the presence of atrophied glomeruli in association with marked inflammatory leucocytes’ infiltration, necrosis and vacuolation of endothelial lining glomerular tuft.

 

As regards the heart, the present study showed that doxorubicin-induced a cardiotoxicity manifested biochemically by a significant increase in serum CK-MB and LDH activities. These results are in agreement with Sahu et al. (2016), Francis and Nayak (2017) and Kim et al. (2017) and also are consistent with the previous study of Yagmurca et al. (2004) who are supporting doxorubicin-inducing cardiotoxicity in normal rats. It could be suggested that increased cardiac enzymes activities in serum might be due to an increase in their release and leakage from cytoplasm of cardiomyocytes to the plasma, following doxorubicin-induced damage of membranes. The elevation of the enzymes related to heart function in the present investigation is concomitant with histological deteriorations which include marked necrosis of cardiomyocytes and inflammatory leukocytic infiltration in heart tissue. In addition the heart sections showed congestion of myocardial blood vessels, vacuolization of sarcoplasm of cardiac myocytes, intermuscular oedema and haemorrhage.

 

The previous deleterious biochemical and histological alterations in the present study of doxorubicin-administered rats are associated with a marked elevation of kidney and heart LPO and a significant decrease of non-enzymatic antioxidant (GSH) content and enzymatic antioxidants including GPx, SOD, and GST enzyme activities. These results are in agreement with many other authors including Abd El-Aziz et al. (2001), Kalender et al. (2005), Yagmurca et al. (2007), Hozayen et al. (2014) and QuanJun et al. (2017) who stated that one of the most prevailing hypotheses of cellular damage from doxorubicin administration is the ability of the drug to produce ROS and suppress antioxidant defense system. They also revealed that the increased LPO play a critical role in in kidney and heart injuries. In the same line, Yeh et al. (2009), Elberry et al. (2010) and Kim et al. (2017) reported that rats injected with doxorubicin showed an increase in the level of kidney and heart LPO and depressed antioxidants such as GSH content and GPx activity. Furthermore, Khan et al. (2005) reported that doxorubicin might cause excessive consumption, reduced production or chemical deactivation of the antioxidant enzymes. The putative role of oxidative stress in the induction of doxorubicin nephritis may be supported by the protective effect of the activation of SOD on the development of doxorubicin nephropathy (Okasora et al., 1992).

 

Doxorubicin-induced renal toxicity due to oxidative stress was elucidated by Yilmaz et al. (2006) and Mohan et al. (2010). According to these publications, doxorubicin-induced severe nephrotic syndrome with massive albuminuria, proteinuria, hyperlipidemia, hypo-albuminemia and hypo-proteinemia associated with a marked suppression in the kidney antioxidant defense and activation of oxidative stress manifested by the increase in kidney LPO and a decrease of kidney GSH content and GPx, GST, SOD activities. The changes reflect many functional alterations such as a drop in glomerular filtration rate, glomerular capillary damage and tubular toxicity as well as approved doxorubicin-induced pathogenesis of nephropathy through involvement of free radicals (Soliman et al., 2014; Badary et al., 2000).

 

That is in agreement with Ganeshpurkar and Saluja (2017) who stated that the increased toxicity of doxorubicin in liver and heart may be due to its ability to deplete the GST. The doxorubicin treatment has actually reduced the activity of GST in a dose dependent manner. They declared also that doxorubicin treatment has been earlier reported to increase the LPO in rat and mice. This evidence was reported also by Papasani et al. (2014), Jagetia and Venkatesh (2017), Jagetia and Venkatesh (2015) and Kwatra et al. (2016).

 

In the present study, the development of oxidative cardiac injury due to multiple doses of doxorubicin was confirmed by the myocardial cell damage, the significant increase in LPO as well as the significant decrease in GSH, GPx, GST, and SOD activities in the heart tissue. These changes in the antioxidant parameters are in accordance with the reports Saad et al. (2001) and Paweorn et al. (2015).

 

Histopathological examination in this study of heart and kidney sections of doxorubicin-administered animals supported the obtained biochemical results. The significant increase in serum creatinine and urea levels in doxorubicin-administered rats was consistent with the doxorubicin-induced deleterious changes in the kidney which exhibited glomerular atrophy and vacuolization of renal glomeruli reflecting the nephrotoxic effects of doxorubicin (Hahn et al., 2004). In the heart, myocardial necrosis, vascular congestion, as well inflammatory cells infiltration. Similar observations have also been revealed in earlier studies on doxorubicin-induced cardiotoxicity (Saad et al., 2001). The myocardial necrosis and damage resulted in an increased leakage of cytoplasmic enzymes CK-MB and LDH into plasma.

 

Polyphenolic compounds are usually found in each edible and inedible plant, and that they are reported to possess multiple biological effects, as well as antioxidant activity. Flavonoids act as antioxidants by neutralizing oxidizing free radicals, including the superoxide and hydroxyl radicals. The redox properties of flavonoids also allow them to act as reducing agents and presence of flavonoids and phenolic compounds have been recognized as excellent scavengers of superoxide, hydroxyl ion and peroxyl radicals by inhibiting LPO. Orange contains phenols and flavonoids which can directly or indirectly reduce oxidative damage by preventing the excessive generation of free radicals (Abdel Moneim, 2014).

 

There are numerous studies showing that rutin decreases doxorubicin-induced cardiotoxicity. In this regard, Yang et al. (2017) stated that suppression of autophagy and apoptosis by administration of rutin could attenuate doxorubicin-induced cardiotoxicity.

 

In our investigation, the elevated creatinine and urea levels in doxorubicin-injected rats significantly decreased as a result of treatment with rutin and quercetin and that are in agreement with previous studies (Nazmi et al., 2016; Jambhulkar et al., 2014).

 

The rutin protective effect against nephrotoxicity can be attributed to its antioxidant and anti-inflammatory effect on ROS and some cytokines may be involved in the glomerular filtration rate damage (Cuzzocrea et al., 2002). This was accompanied by the improvement in serum creatinine, urea and uric acid levels and was associated with a decrease of LPO and an increase in GSH in the kidney. The attenuation of glutathione depleting effects of doxorubicin by quercetin in blood, heart and kidney tissues reveals the antioxidant effects produced by this flavonoid. The reduction (P< 0.01) in levels of MDA in kidney tissues of doxorubicin-injected rats pretreated with quercetin suggests the anti-lipid peroxidative property of test drug (Nazmi et al., 2016). Therefore, rutin and/or quercetin can protect the kidney from doxorubicin-induced injury via improvement in oxidant status.

 

In the present study, rutin and quercetin also reduced the elevated activities of serum enzymes related to the heart function including CK-MB and LDH in doxorubicin-injected rats. These findings are in agreement with Nazmi et al. (2016) who indicated that the pretreatment with quercetin resulted in significant reduction in the activities of AST and LDH toward near normal as compared with toxic control rats. This result could be due to protective effects of quercetin on the myocardium; thereby restricting the leakage of AST and LDH. These results were accompanied with decrease in heart LPO and elevation in GSH content as well as increase in GPx, GST and SOD activities. Thus, it can be suggested that the suppression of LPO and oxidative stress may be implicated in the improvements of the heart function and histological integrity as a result of treatment of doxorubicin-administered rats with rutin and quercetin.

 

Histopathological examination in this study of kidney and heart sections of doxorubicin-administered animals treated with rutin supports the above mentioned biochemical results. Kidney sections of doxorubicin-injected rats treated with rutin showed mild focal mononuclear inflammatory cells’ infiltration in some animals and showed no hisopathological changes in others. The treatment of doxorubicin-administered rats with quercetin produced mild congestion of renal intertubular blood vessels, vacuolation of endothelial lining glomerular tuft in some animals and showed no hisopathological changes in others. The treatment of doxorubicin-administered rats with a combination of rutin and quercetin exhibited more improvement of the kidney histological changes as compared with doxorubicin-administered control. It exhibited no histopathological changes. Heart sections of doxorubicin-administered rats treated with rutin showed vacuolation of sarcoplasm of cardiac myocytes in some animals and no histopathological changes in others. The treatment of doxorubicin-injected rats with quercetin or its combination with rutin produced no histopathological changes.

 

CONCLUSION

 

Both rutin and/or quercetin successfully prevented doxorubicin-induced kidney and heart injuries manifested by improvement in the function and histological integrity of kidney and heart. These preventive effects may be mediated via suppression of oxidative stress and inflammation as well as enhancement of the antioxidant defense system.

 

ACKNOWLEDGEMENT

 

The authors deeply thank Prof. Dr. Kawkab A. Ahmed, Professor of Histopathology, Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt for help in examining and identifying lesions in the histological sections.

 

Authors Contribution

 

Heba Uallah R. Mahmoud performed the experimental work and participated in writing the draft of the manuscript; Osama M. Ahmed proposed the research plan, guided the experimental work and shared in writing and revising the manuscript. Hanaa I. Fahim revised the manuscript and also supervised the experimental work; Noha A. Ahmed participated in following up the experimental work and shared in writing and revising the manuscript; and Mohamed B. Ashour revised the manuscript and also supervised the experimental work. 

 

Conflict of interest

 

The authors declare that there no conflict of interest.

 

REFERENCES

 

  • Abdel Moneim A (2014). Citrus peel extract attenuates acute cyanide poisoning-induced seizures and oxidative stress in rats. CNS Neurol. Disord. Drug Targets. 13(4): 638-646. https://doi.org/10.2174/1871527312666131206095142
  • AbdEl-Aziz M, Othman A, Amer M, El-Missiry M (2001). Potential protective role of angiotensin-converting enzyme inhibitors captopril and enalapril against adriamycin-induced acute cardiac and hepatic toxicity in rats. J. Appl. Toxicol. 21: 469-473. https://doi.org/10.1002/jat.782
  • Abou Seif H (2012). Protective Effects of Rutin and Hesperidin against Doxorubicin-Induced Nephrotoxicity. Beni-Suef Univ. J. Appl. Sci. 1(2): 1–18.
  • Ahmed MA (2013). The Protective Effect of Ginger (Zingiber Officinale) against adriamycin-induced hepatotoxicity in rats: Histological study. Life. Sci. J. 10(1): 1412-1422.
  • Ahmed OM, Ashour MB, Abd Wl-Fattah, AS (2017). The Preventive effects of navel orange peel ethanolic extract and naringin on doxorubicin-induced nephrocardiotoxicity in male albino rats. Indo Am. J. Pharm. Res. 7(07): 109-117.
  • Ahmed OM, Abdul-Hamid MM, El-Bakry AM, Mohamed HM, Abdel Rahman FS (2019). Effects of green tea infusion and epicatechin on doxorubicin-induced renocardiotoxicity in male albino rats. IJPSR, 10(5):1000–1014.
  • Ahmed SI, Hayat MQ, Tahir M, Mansoor Q, Ismail M, Keck K, Bates RB (2016). Pharmacologically active flavonoids from the anticancer, antioxidant and antimicrobial extracts of Cassia angustifolia Vahl. BMC Complement. Altern. Med. 16: 460. https://doi.org/10.1186/s12906-016-1443-z
  • Andreu L, Nuncio-Jáuregui N, Carbonell-Barrachina Á, Legua P, Hernández F (2018). Antioxidant properties and chemical characterization of Spanish Opuntia ficus-indica Mill. Cladodes and fruits. J. Sci. Food Agric. 98: 1566–1573. https://doi.org/10.1002/jsfa.8628
  • Ayla S, Seckin I, Tanriverdi G, Cengiz M, Eser M, Soner B, Oktem G (2011). Doxorubicin induced nephrotoxicity protective effect of nicotinamide. Int. J. Cell Biol. (390238): 9. https://doi.org/10.1155/2011/390238
  • Badary OA, Abdel-naim AB, Abdel-wahab MH, Hamada FM (2000). The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. Toxicology. 143: 219–226. https://doi.org/10.1016/S0300-483X(99)00179-1
  • Banchroft J, Stevens A, Turner D (1996). Theory and practice of histological techniques. Fourth edition, Churchillivingstone, New York, London, San Francisco, Tokyo. pp. 766.
  • Beutler E, Duren O and Kelly B (1963). Improved method for the determination of blood glutathione. J. Lab. Clin. Med. 61: 882-888.
  • Bo L, Liu Y, Jia S, Liu Y, Sun C. (2018). Metabonomics analysis of quercetin against the nephrotoxicity of acrylamide in rat. Food Funct., 9: 5965-5974. https://doi.org/10.1039/C8FO00902C
  • Cao B, Li M, Zha W, Zhao Q, Gu R, Liu L, Shi J, Zhou J, Zhou F, Wu X, Wu Z, Wang G and Aa J (2013). Metabolomic approach to evaluating adriamycin pharmacodynamics and resistance in breast cancer cells. Metabolomics. 9: 960–973. https://doi.org/10.1007/s11306-013-0517-x
  • Cappetta D, De Angelis A, Sapio L, Prezioso L, Illiano M, Quaini F, Rossi F, Berrino L, Naviglio S and Urbanek K (2017). Oxidative stress and cellular response to doxorubicin: a common factor in the complex milieu of anthracycline cardiotoxicity. Oxid. Med. Cell. Longevity. (1521020): 13. https://doi.org/10.1155/2017/1521020
  • Chio I and Tuveson D, ROS in Cancer (2017). The Burning Question. Trends Mol. Med. 23: 411–429. https://doi.org/10.1016/j.molmed.2017.03.004
  • Choi H, Gao X and Curhan G (2009). Vitamin C intake and the risk of gout in men: a prospective study. Arch. Int. Med. 169: 502-507. https://doi.org/10.1001/archinternmed.2008.606
  • Coldwell K, Cutts SM, Ognibene TJ, Henderson PT, Phillips DR (2010). Detection of adriamycin-DNA adducts by accelerator mass spectrometry. Met. Mol. Biol. 613: 103–118. https://doi.org/10.1007/978-1-60327-418-0_7
  • Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Di Paola R, Britti, D. De Sarro A, Pierpaoli S, Caputi AP, Masini E, Salveminie D (2002). A role for superoxide in gentamicin-mediated nephropathy in rats. Eur. J. Pharmacol. 450(1): 67–76. https://doi.org/10.1016/S0014-2999(02)01749-1
  • Działo M, Mierziak J, Korzun U, Preisner M, Szopa J, Kulma A (2016). The potential of plant phenolics in prevention and therapy of skin disorders. Int. J. Mol. Sci. 17: 160. https://doi.org/10.3390/ijms17020160
  • Elberry AA, Abdel-Naim AB, Abdel-Sattar EA, Nagy AA, Mosli HA, Mohamadin AM and Ashour OM (2010). Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats. Food Chem. Toxicol. 48: 1178-1184. https://doi.org/10.1016/j.fct.2010.02.008
  • El-Moselhy M, El-Sheikh A (2014). Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity. Biomed. Pharmacother. 68(1): 101–110. https://doi.org/10.1016/j.biopha.2013.09.001
  • Ferreira A, CunhaOliveira T, Simões RF, Carvalho FS, Burgeiro A, Nordgren K, Wallace KB, Oliveira PJ (2017). Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity. Toxicol. 390: 63–73. https://doi.org/10.1016/j.tox.2017.08.011
  • Francis A and Nayak Y (2017). Modulation of Doxorubicin-Induced Cardiotoxicity by Averrhoa bilimbi extract. J. Young Pharm. 9(1): 70-78. https://doi.org/10.5530/jyp.2017.9.14
  • Ganeshpurkar A and Saluja A (2017). The pharmacological potential of rutin, Saudi Pharm. J. 25(2): 149–164. https://doi.org/10.1016/j.jsps.2016.04.025
  • Gharanei M, Hussain A, James RS, Janneh O, Maddock H (2014). Investigation into the cardiotoxic effects of doxorubicin on contractile function and the protection afforded by cyclosporine A using the work-loop assay. Toxicol. in Vitro. 28(5): 722–731. https://doi.org/10.1016/j.tiv.2014.01.011
  • Gokcimen A, Cim A, Tola HT, Bayram D, Kocak A, Ozgüner F, Ayata A. (2007). Protective effect of N-acetylcysteine, caffeic acid and vitamin E on doxorubicin hepatotoxicity. Hum. Exp. Toxicol. 26: 519-525. https://doi.org/10.1177/0960327107076885
  • Guardia T, Rotelli AE, Juarez AO, Pelzer LE (2001). Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. I l Farmaco. 56 (9): 683-687. https://doi.org/10.1016/S0014-827X(01)01111-9
  • Hahn H, Park Y, Ha I Cheong H, Choi Y (2004). Age-related differences in adriamycin-induced nephropathy. Pediatr. Nephrol. 19: 761–766. https://doi.org/10.1007/s00467-004-1487-z
  • Hozayen WG, Abou Seif H, Amin S (2014). Protective Effects of Rutin and / or Hesperidin against Doxorubicin-Induced Hepatotoxicity. Int. J. Clin. Nutr.. 2 (1): 11-17.
  • Hozayen WG, Ahmed OM, Abo Sree HT (2013). Effects of purslane shoot and seed ethanolic extracts on doxorubicin-induced testicular toxicity in albino rats. Life Sci. J. 10(3): 2550-2558.
  • Huang HY, Appel LJ, Choi MJ, Gelber AC (2005). The effects of vitamin C supplementation on serum concentrations of uric acid: Results of a randomized controlled trial. Arthritis Rheum. 52: 1843–1847. https://doi.org/10.1002/art.21105
  • Injac R, Perse M, Obermajer N, Djordjevic-Milic V, Prijatelj M, Djordjevic A, Cerar A, Strukelj B (2008). Potential hepatoprotective effects of fullerenol C60 (OH) 24 in doxorubicin-induced hepatotoxicity in rats with mammary carcinomas. Biomaterials. 29 (24-25): 3451-3460. https://doi.org/10.1016/j.biomaterials.2008.04.048
  • Jabłonska-Trypuc A, ´Swiderski G, Kretowski R, Lewandowski W (2017). Newly synthesized doxorubicin complexes with selected metals-synthesis, structure and anti-breast cancer activity. Molecules. 22: 1106. https://doi.org/10.3390/molecules22071106
  • Jacevic V, Dragojevic-Simic V, Tatomirovic Z, Dobric S, Bokonjic D, Kovacevic A, Nepovimova E, Vališ M, Kuča K (2018). The Efficacy of Amifostine against Multiple-Dose Doxorubicin-Induced Toxicity in Rats. Int. J. Mol. Sci. 19: 2370. https://doi.org/10.3390/ijms19082370
  • Jagetia GC, Lalrinengi C (2017). Treatment of mice with naringin alleviates the doxorubicin-induced oxidative stress in the liver of Swiss albino mice. MOJ Anat. Physiol. 4(2): 267‒278. https://doi.org/10.15406/mojap.2017.04.00130
  • Jagetia GC, Venkatesh P (2015). An indigenous plant bael (Aegle marmelos (L.) Correa) extract protects against the doxorubicin-induced cardiotoxicity in mice. Biochem. Physiol. 4: 3. https://doi.org/10.4172/2168-9652.1000163
  • Jambhulkar S, Deshireddy S, Jestadi D, Periyasamy L (2014). Quercetin Attenuating Doxorubicin Induced Hepatic, Cardiac and Renal Toxicity in Male Albino Wistar Rats. Am. J. Phytomed. Clin. Ther. AJPCT. 2(8): 985-1004.
  • Kalender Y, Yel M, Kalender S (2005). Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicol. 209: 39-45. https://doi.org/10.1016/j.tox.2004.12.003
  • Karaman A, Fadillioglu E, Turkmen E, Tas E, Yilmaz Z (2006). Protective effects of leflunomide against ischemia reperfusion injury of the rat liver. Pediatr. Surg. Int., 22: 428–434. https://doi.org/10.1007/s00383-006-1668-x
  • Khan M, Shobha JC, Mohan IK, Naidu MU, Sundaram C, Singh S, Kuppusamy P, Kutala VK (2005). Protective effect of Spirulina against doxorubicin-induced cardiotoxicity in mice. Phytother. Res. 19: 1030 –1037. https://doi.org/10.1002/ptr.1783
  • Kim SH, Kim K, Kim J, Kwak J, Song H, Cho JY, Hwang DY, Kim KS, Jung Y (2017). Comparision of doxorubicin-induced cardiotoxicity in the ICR mice of different sources. Lab. Anim. Res. 33: 165–170. https://doi.org/10.5625/lar.2017.33.2.165
  • Kumar S, Pandey AK (2013a). Chemistry and biological activities of flavonoids: An overview. Sci. World J. pp. 162750. https://doi.org/10.1155/2013/162750
  • Kumar S, Pandey AK (2013b). Phenolic content, reducing power and membrane protective activities of Solanum xanthocarpum root extracts. Vegetos. 26: 301–307. https://doi.org/10.5958/j.2229-4473.26.1.043
  • Kuznetsova AV, Margreiter R, Amberger A, Saks V and Grimm M (2011). Changes in mitochondrial redox state, membrane potential and calcium precede mitochondrial dysfunction in doxorubicin -induced cell death, Biochimica et Biophysica Acta (BBA) – Molecular cell Research. 1813(6): 1144-1152. https://doi.org/10.1016/j.bbamcr.2011.03.002
  • Kwatra M, Kumar V, Jangra A, Mishra M, Ahmed S, Ghosh P, Vohora D, Khanam R (2016). Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. Pharm. Biol. 54(4): 637‒647. https://doi.org/10.3109/13880209.2015.1070879
  • Lakhanpal P, Rai DK (2007). Quercetin A versatile flavonoid. Int. J. Med. Update. 2: 22-37. https://doi.org/10.4314/ijmu.v2i2.39851
  • Lamson DW, Brignall MS (2000). Antioxidants and cancer, part 3: Quercetin. Altern. Med. Rev. 5: 196-208.
  • Liu G, Liu Y, Wang R, Hou T, Chen C, Zheng S, Dong Z (2016). Spironolactone attenuates doxorubicin-induced cardiotoxicity in rats. Cardiovasc Ther. 34: 216–224. https://doi.org/10.1111/1755-5922.12189
  • Lorenzo E, Ruiz-Ruize C, Quesada AJ, Hernandez G, Rodriguez A, Lopez-Rivas A, Redondo JM (2002). Doxorubicin induces apoptosis and CD 95 gene expression in human primary endothelial cells through a p 53-depenent mechanism. J. Biol. Chem., 277: 10883-10892. https://doi.org/10.1074/jbc.M107442200
  • Luo H, Jiang N, King SM, Chen YC (2008). Inhibition of Cell Growth and VEGF Expression in Ovarian Can Cells by Flavonoids. Nutr. Cancer. 60 (6): 800-809. https://doi.org/10.1080/01635580802100851
  • Lv S, Li M, Tang Z, Song W, Sun H, Liu H, Chen X (2013). Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy. Acta Biomater. 9 (12): 9330–9342. https://doi.org/10.1016/j.actbio.2013.08.015
  • Mandziuk S, Gieroba R, Korga A, Matysiak W, Jodlowska-Jedrych B, Burdan F, Poleszak E, Kowalczyk M, Grzycka-Kowalczyk L, Korobowicz E, Jozefczyk A, Dudka J (2015). The differential effects of green tea on dose-dependent doxorubicin toxicity. Food Nutr. Res. 59: 29754. https://doi.org/10.3402/fnr.v59.29754
  • Mannervik B, Guthenberg C (1981). Glutathione transferase (Human placenta). Methods Enzymol. 77: 231-235. https://doi.org/10.1016/S0076-6879(81)77030-7
  • Marklund S, Marklund G (1974). Involvement of the superoxide anion radical in the autoxidation of pyrogallol and convenient assay for superoxide dismutase. Eur. J. Biochem. 47: 469-474. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x
  • Matkovics B, Kotorman M, Varga I, Hai D, Varga C (1998). Oxidative stress in experimental diabetes induced by streptozotocin. Acta Physiol. Hung. 85: 29-38.
  • Meng X, Liu C, Fan R, Zhu L, Yang S, Zhu H, Wang D, Yang C, Zhang Y (2018). Antioxidative flavan-3-ol dimers from the leaves of Camellia fangchengensis. J. Agric. Food Chem. 66: 247–254. https://doi.org/10.1021/acs.jafc.7b04572
  • Mesquita C, Leão M (2018). Cardiology and sustainable development. Int. J. Cardiovasc Sci. 31(1): 1-3.
  • Mishra S, Jha AB, Dubey RS (2011). Arsenite treatment induces oxidative stress, upregulates antioxidant system, and causes phytochelatin synthesis in rice seedlings. Protoplasma, Protoplasma. 248 (3): 565–577. https://doi.org/10.1007/s00709-010-0210-0
  • Mohan M, Kamble S, Gadhi P, Kasture S (2010). Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats. Food Chem. Toxicol. 48(1): 436-440. https://doi.org/10.1016/j.fct.2009.10.042
  • Nazmi AS, Ahmad SJ, Pillai KK, Akhtar M, Ahmad A, Najmi A (2016). Protective effects of Bombyx mori, quercetin and benazepril against doxorubicin induced cardiotoxicity and nephrotoxicity.” J. Saudi Chem. Soc. 20: 573–578. https://doi.org/10.1016/j.jscs.2013.04.001
  • Okasora T, Takikawa T, Utsunomiya Y, Senoh I, Hayashibara H, Shiraki K, Kasagi T and Shimizu F (1992). Suppressive effect of superoxide dismutase on adriamycin nephropathy. Nephron. 60: 199–203. https://doi.org/10.1159/000186739
  • Olas B, Wachowicz B (2002). Resveratol and vitamin C as antioxidant in blood platelets. Thromb. Res. 106: 143-148. https://doi.org/10.1016/S0049-3848(02)00101-9
  • Papasani VM, Hanumantharayappa B, Annapurna A (2014). Cardioprotective effect of naringin against doxorubicin induced cardiomyopathy in rats. Indo Am. J. Pharm. Res. 4(5): 2593‒2598.
  • Patel N, Joseph C, Corcoran GB, Ray SD (2010). Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p 53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol. Appl. Pharmacol. 245(2): 143-152. https://doi.org/10.1016/j.taap.2010.02.002
  • Paweorn A, Sudjit L, Surapol I (2015). Chemotherapy-induced cardiotoxicity (2015). Overview of the roles of oxidative stress. Oxidative Med. Cell. Longevity. pp. 1-13. https://doi.org/10.1155/2015/795602
  • Rao M, Blane K, Zonneberg M (1985). PC-STAT. One-way analysis of variance. Version 1A (C) copyright. The University of Georgia. Programs coded by University of Georgia, USA.
  • Poornima P, Kumar VB, Weng CF, Padma VV (2014). Doxorubicin induced apoptosis was potentiated by neferine in human lung adenocarcima, A549 cells. Food Chem. Toxicol. 68: 87–98. https://doi.org/10.1016/j.fct.2014.03.008
  • Preuss H, Jarrel S, Scheckenbach R, Lieberman S, Anderson R (1998). Comparative effects of chromium, vanadium and Gymnema sylvestre on sugar-induced blood pressure elevations in SHR. J. Am. Coll. Nutr. 17: 116-123. https://doi.org/10.1080/07315724.1998.10718736
  • QuanJun Y, GenJin Y, LiLi W, YongLong H,Yan H, Jie L, JinLu H, Jin L, Run G, Cheng G (2017). Protective Effects of Dexrazoxane against Doxorubicin-Induced Cardiotoxicity: A Metabolomic Study. PLoS ONE. 12(1): 0169567. https://doi.org/10.1371/journal.pone.0169567
  • Quiles JL, Huertas JR, Battino M, Mataix J, Ramirez-Tortosa MC (2002). Antioxidant nutrients and adriamycin toxicity. Toxicol.180: 79-95. https://doi.org/10.1016/S0300-483X(02)00383-9
  • Saad SY, Najja TA, Al-Rikabi AC. (2001). The preventive role of deferoxamine against acute doxorubicin induced cardiac, renal and hepatic toxicity in rats. Pharmacol. Res., 43: 211-218. https://doi.org/10.1006/phrs.2000.0769
  • Safdar M, Kausar T, Nadeem M, Jabbar S, Ahmed S, Taj T, Tufail F, Mehmood W (2017). Cardioprotective effect of mango and kinnow peel extracts on doxorubicin-induced cardiotoxicity in Albino Rats.” Proc. Pak. Acad. Sci. Pak. Acad. Sci. B. Life Environ. Sci. 54 (3): 219–235.
  • Sahin K, Sahin N, Kucuk O (2010). Lycopene and chemotherapy toxicity. Nutr. Cancer. 62 (7): 988– 995. https://doi.org/10.1080/01635581.2010.509838
  • Sahu BD, Kumar JM, Kuncha M, Borkar RM, Srinivasc R, Sistla R (2016). Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice. Life Sci. 144: 8-18. https://doi.org/10.1016/j.lfs.2015.11.018
  • Sathesh KV, Sharmila S, Premkumar T, Palanisamy K, Sauter K, Magun EA, Iordanov MS, Magun BE (2010). ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells. Cancer Biol., Ther. 10: 258–266.
  • Selvakumar E, Prahalathan C, Sudharson PT and Viralakshmi P (2006). Protective effect of lipoic acid on micronuclei induction by cyclophosphamide. Arch. Toxicol. 80(2): 115-119. https://doi.org/10.4161/cbt.10.3.12367
  • Shiromwar SS, Chidrawar VR (2011). Combined effects of p-coumaric acid and naringenin against doxorubicin-induced cardiotoxicity in rats. Pharmacogn. Mag. 3 (3): 214-219. https://doi.org/10.4103/0974-8490.85012
  • Soliman HA, Ahmed RR, Gomaa HA, Ali AT (2014). Assessment of the chemo-preventive effects of various plant constituents against doxorubicin-induced toxicity in Rats. J. Am. Sci. 10(9): 153-164.
  • Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S. 2019. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol. Lett. 2019 Published online 2019 Feb. https://doi.org/10.1016/j.toxlet.2019.02.013
  • Srivastava S, Dubey RS (2011). Manganese-excess induces oxidative stress, lowers the pool of antioxidants and elevates activities of key antioxidative enzymes in rice seedlings Plant Growth Regulation. 64(1): 1–16. https://doi.org/10.1007/s10725-010-9526-1
  • Suganya SN, Sumathi T (2016). Rutin a dietary flavonoid protects against altered neurobehavioral, membrane bound enzymes and striatal damage induced by 3- nitropropionic acid in male wistar rats. Int. J. Pharmacogn. Phytochem. Res. 8(7): 1191-1199.
  • Ta HQ, Thomas KS, Schrecengost RS, Bouton AH (2008). A novel association between p130 Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. Cancer Res. 68: 8796–8804. https://doi.org/10.1158/0008-5472.CAN-08-2426
  • Takemura G, Fujiwara H (2007). Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog. Cardiovasc. Dis. 49: 330-352. https://doi.org/10.1016/j.pcad.2006.10.002
  • Taskin E, Dursun N (2015). Recovery of adriamycin induced mitochondrial dysfunction in liver by selenium. Cytotechnology. (67): 977–986. https://doi.org/10.1007/s10616-014-9736-x
  • Trivedi PP, Kushwaha S, Tripathi DN, Jena GB (2011). cardioprotective effects of Hesperetin against Doxorubicin-induced oxidative stress and DNA damage in rat. Food Chem. Toxicol. 11(3): 215-225. https://doi.org/10.1007/s12012-011-9114-2
  • World Health Organization (WHO) (2018). Global Health Observatory. Geneva: World Health Organization (2018). who.int/gho/database/en/. Accessed June 21, 2018.
  • Xin Z, Jiang S, Jiang P, Yan X, Fan C, Di S, Wu G, Yang Y, Reiter RJ, Ji G (2015). Melatonin as a treatment for gastrointestinal cancer: a review. J. Pineal Res. 58(4): 375–387. https://doi.org/10.1111/jpi.12227
  • Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O (2007). Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch. Med. Res., 38: 380-385. https://doi.org/10.1016/j.arcmed.2007.01.007
  • Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M, Fadillioglu E (2004). Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin. Chim. Acta. 348(1- 2): 27-34. https://doi.org/10.1016/j.cccn.2004.03.035
  • Yang L, Ma J, Ma Y, Lu L, Wang X, Ren J, Yang J (2017). Rutin attenuates doxorubicin-induced cardiotoxicity via regulating autophagy and apoptosis. Biochim. Biophys. Acta. 1863: 1904–1911. https://doi.org/10.1016/j.bbadis.2016.12.021
  • Yapislar H, Taskin E, Ozdas S, Akin D, Sonmez E (2016). Counteraction of apoptotic and inflammatory effectsof adriamycin in the liver cell culture by clinopitolite. Biol. Trace Elem. Res. (170): 373–381. https://doi.org/10.1007/s12011-015-0476-3
  • Yeh YC, Liu TJ, Wang, LC, Lee HW, Ting CT, Lee WL, Hung CJ, Wang KY, Lai HC (2009). A standardized extract of Ginkgobiloba suppresses doxorubicin-induced oxidative stress and P53-mediated mitochondrial apoptosis in rats testes. Br. J. Pharmacol. 156(1): 48–61. https://doi.org/10.1111/j.1476-5381.2008.00042.x
  • Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S (2006). Protective effect of lycopene on adriamycin-induced nephrotoxicity and nephrotoxicity. Toxicology. 218: 164–171. https://doi.org/10.1016/j.tox.2005.10.015
  • Young D (1990). Effects of drugs on clinical laboratory tests AACC press, Washington D.C.
  • Young D (1995). Effects of drugs on clinical laboratory tests. 4th ed.
  • Young D (2001). Effects of disease on Clinical Lab. Tests, AACC.
  •  

     

     

    Advances in Animal and Veterinary Sciences

    November

    Vol. 12, Iss. 11, pp. 2062-2300

    Featuring

    Click here for more

    Subscribe Today

    Receive free updates on new articles, opportunities and benefits


    Subscribe Unsubscribe