Volume 32, Issue 1 (3-2025)
RJMS 2025, 32(1): 1-14 |
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Research code: 1400-3-105-22066
Ethics code: IR.IUMS.FMD.REC.1400.588
Clinical trials code: no
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Ghasemi A, Safaei A, Sheibani M, Mohammadkhanizadeh A, Azizi Y. Effects of Apigenin on Liver and Lung Toxicity Caused by Doxorubicin in Male Rats. RJMS 2025; 32 (1) :1-14
URL: http://rjms.iums.ac.ir/article-1-8432-en.html
URL: http://rjms.iums.ac.ir/article-1-8432-en.html
Ph.D., Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran , azizi.y@iums.ac.ir
Abstract: (1495 Views)
Background & Aims: Doxorubicin (Adriamycin; DOX), the anthracycline antibiotic, was first produced from Streptomyces peucetius var. caesius in 1960. Doxorubicin is used in the treatment of various types of malignancies including lymphoma, leukemia and solid tumors including lung, breast, and bladder cancers. Cardiac myocytes are potentially more susceptible to the long-term adverse effects of chemotherapy agents such as doxorubicin due to the less regeneration ability in cardiac cells. Although cardiac toxicity is the main side effect of this drug, liver and lung toxicity have also been reported. Also, it has been reported that DOX is implicated in pulmonary toxicity. Although pulmonary toxicity prompted by DOX has not been proficiently characterized, oxidative stress signaling has been included as the foremost reason of this toxicity. Moreover, liver dysfunction or liver toxicity also are commonly associated with DOX administration.
Apigenin is a flavonoid found in different type of herbs, fruits, and vegetables such as chamomile, parsley, celery, and basil. Various flavonoid interactions with multiple cellular mechanisms allow apigenin to modify cellular regulatory pathways that change the behavior of all cells. These pathways include several cell cycle-related cascades such as proliferation and differentiation, growth, apoptosis, and autophagy. Apigenin has various beneficial health effects, including antioxidant, anti-inflammatory, antiviral, antibacterial, anti-carcinogenic, neuroprotective, and cardioprotective which exert beneficial effects in preventing a wide variety of chronic diseases, promoting health, and enhancing therapeutic efficacy. One study showed that apigenin prevents DOX-induced damage and improves myocardial function through antioxidant effects. The aim of this study was to investigate the effects of apigenin on liver and lung toxicity caused by DOX and the possible role of nitric oxide.
Methods: 60 male Wistar rats were randomly divided into 6 groups (n=10). Control group (animals received vehicle without any intervention), apigenin (animals received daily administration of 50 mg/kg for 2 weeks), DOX (animals received 6 repeated 12 mg/kg DOX every other day for two weeks), apigenin+DOX (animals received 6 repeated 12 mg/kg DOX every other day and daily injection of 50 mg/kg apigenin for 2 weeks), DOX+L-NAME (animals received 6 repeated 12 mg/kg DOX every other day and daily injection of 30 mg/kg L-NAME for 2 weeks), and DOX+apigenin+L-NAME (animals received 6 repeated 12 mg/kg DOX every other day, daily injection of 30 mg/kg L-NAME, and 50 mg/kg apigenin for 2 weeks). For induction of liver and lung toxicity in groups 3, 4, 5, and 6, DOX was injected intraperitoneally (i.p.) in 6 doses of 2 mg/kg every 48 hours. Apigenin was administered orally (p.o) with a dose of 50 mg/kg in groups 2, 4, and 6. To prevent the formation of nitric oxide (NO), L-NAME was injected i.p. in groups 5 and 6 at 6 doses of 30 mg/kg every 48 hours. At the end of 2 weeks, the animals were anesthetized by ketamine (75 mg/kg) and xylazine (5 mg/kg). Then, the liver and lung tissues were separated and fixed in formalin 10% solution for assessment of tissue damages by H&E staining and tissue fibrosis by Masson trichrome staining. Also, the serum samples were collected for evaluating levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) for evaluating liver function.
Results: Data analysis showed that apigenin could prevent tissue changes caused by DOX in liver and lung tissues. Neutrophil infiltration, tissue disarrangement, hemorrhage, and inflammatory alterations were significantly lower in apigenin-received group than DOX group. The histopathological changes were consistent with DOX-induced lung damage. Apigenin also reduced lung fibrosis (p<0.05) and collagen deposition. Administration of L-NAME could significantly reverse protective effects of apigenin in lung fibrosis. On the other hand, inhibition of NO by L-NAME prevented almost all protective effects of apigenin. Moreover, apigenin could improve weight loss associated with DOX toxicity. DOX injection and apigenin treatment did not cause significant changes in liver enzymes (AST and ALT) and liver fibrosis.
Conclusion: From these results, we can conclude that there exists a strong correlation between the use of DOX and risk for developing hepatotoxicity and lung toxicity. There are multiple reasons for DOX-induced hepatotoxicity and lung toxicity. Apigenin, as a potent anti-inflammatory agent, could reduce the lung and liver tissue damages induced by DOX, decrease the degree of lung fibrosis, and enhance body weight of animals after receiving DOX. It seems that inhibition of nitric oxide by L-NAME administration decreases the protective effects of apigenin. Apigenin probably exerts a part of its protective effects against liver and lung toxicity caused by DOX by increasing the expression of NO. More investigations and researches are needed for discovering all aspects of apigenin protective mechanisms in DOX-induced organ damages.
Apigenin is a flavonoid found in different type of herbs, fruits, and vegetables such as chamomile, parsley, celery, and basil. Various flavonoid interactions with multiple cellular mechanisms allow apigenin to modify cellular regulatory pathways that change the behavior of all cells. These pathways include several cell cycle-related cascades such as proliferation and differentiation, growth, apoptosis, and autophagy. Apigenin has various beneficial health effects, including antioxidant, anti-inflammatory, antiviral, antibacterial, anti-carcinogenic, neuroprotective, and cardioprotective which exert beneficial effects in preventing a wide variety of chronic diseases, promoting health, and enhancing therapeutic efficacy. One study showed that apigenin prevents DOX-induced damage and improves myocardial function through antioxidant effects. The aim of this study was to investigate the effects of apigenin on liver and lung toxicity caused by DOX and the possible role of nitric oxide.
Methods: 60 male Wistar rats were randomly divided into 6 groups (n=10). Control group (animals received vehicle without any intervention), apigenin (animals received daily administration of 50 mg/kg for 2 weeks), DOX (animals received 6 repeated 12 mg/kg DOX every other day for two weeks), apigenin+DOX (animals received 6 repeated 12 mg/kg DOX every other day and daily injection of 50 mg/kg apigenin for 2 weeks), DOX+L-NAME (animals received 6 repeated 12 mg/kg DOX every other day and daily injection of 30 mg/kg L-NAME for 2 weeks), and DOX+apigenin+L-NAME (animals received 6 repeated 12 mg/kg DOX every other day, daily injection of 30 mg/kg L-NAME, and 50 mg/kg apigenin for 2 weeks). For induction of liver and lung toxicity in groups 3, 4, 5, and 6, DOX was injected intraperitoneally (i.p.) in 6 doses of 2 mg/kg every 48 hours. Apigenin was administered orally (p.o) with a dose of 50 mg/kg in groups 2, 4, and 6. To prevent the formation of nitric oxide (NO), L-NAME was injected i.p. in groups 5 and 6 at 6 doses of 30 mg/kg every 48 hours. At the end of 2 weeks, the animals were anesthetized by ketamine (75 mg/kg) and xylazine (5 mg/kg). Then, the liver and lung tissues were separated and fixed in formalin 10% solution for assessment of tissue damages by H&E staining and tissue fibrosis by Masson trichrome staining. Also, the serum samples were collected for evaluating levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) for evaluating liver function.
Results: Data analysis showed that apigenin could prevent tissue changes caused by DOX in liver and lung tissues. Neutrophil infiltration, tissue disarrangement, hemorrhage, and inflammatory alterations were significantly lower in apigenin-received group than DOX group. The histopathological changes were consistent with DOX-induced lung damage. Apigenin also reduced lung fibrosis (p<0.05) and collagen deposition. Administration of L-NAME could significantly reverse protective effects of apigenin in lung fibrosis. On the other hand, inhibition of NO by L-NAME prevented almost all protective effects of apigenin. Moreover, apigenin could improve weight loss associated with DOX toxicity. DOX injection and apigenin treatment did not cause significant changes in liver enzymes (AST and ALT) and liver fibrosis.
Conclusion: From these results, we can conclude that there exists a strong correlation between the use of DOX and risk for developing hepatotoxicity and lung toxicity. There are multiple reasons for DOX-induced hepatotoxicity and lung toxicity. Apigenin, as a potent anti-inflammatory agent, could reduce the lung and liver tissue damages induced by DOX, decrease the degree of lung fibrosis, and enhance body weight of animals after receiving DOX. It seems that inhibition of nitric oxide by L-NAME administration decreases the protective effects of apigenin. Apigenin probably exerts a part of its protective effects against liver and lung toxicity caused by DOX by increasing the expression of NO. More investigations and researches are needed for discovering all aspects of apigenin protective mechanisms in DOX-induced organ damages.
Type of Study: Research |
Subject:
Hematology & oncology
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