Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis.
Methotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid drug whose efficacy is limited by its hepatotoxicity. The aim of this study was to investigate the possible protective role of captopril (100 mg/kg/day, p.o. for seven days), an angiotensin converting enzyme inhibitor, and telmisartan (10 mg/kg/day p.o. for seven days), an angiotensin II receptor blocker with peroxisome proliferative receptor gamma (PPARγ) agonism, in a model of MTX (single dose 20 mg/kg i.p. at the fifth day) induced hepatotoxicity in rats. Results of the present study revealed MTX-induced hepatotoxicity as demonstrated by increased level of liver enzymes and confirmed by histopathology. Pretreatment with captopril or telmisartan produced a significant hepatic protection manifested as a significant (p < 0.05) decrease in serum levels of alanine transferase (ALT) and aspartate transferase (AST) and alkaline phosphatase (ALP) enzymes; hepatic malondialdehyde (MDA) and total nitrites and nitrates (NOx) levels; as well as a significant increase in hepatic superoxide dismutase (SOD) activity. In addition, there was a remarkable improvement in the histopathological features and a significant reduction in the expression of COX-2, iNOS and caspase-3 enzymes as compared with the MTX group. We recommend considering captopril/Telmisartan, if tolerated and not contraindicated, as preferable antihypertensive agents in patients receiving MTX in their chemotherapy protocols.
a Faculty of Medicine, Department of Pharmacology , Minia University , Minia , Egypt.
Mina T
MT
Kelleni
a Faculty of Medicine, Department of Pharmacology , Minia University , Minia , Egypt.
Salwa A
SA
Ibrahim
a Faculty of Medicine, Department of Pharmacology , Minia University , Minia , Egypt.
Aly M
AM
Abdelrahman
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D001565:Benzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D002216:Captopril / Q000008:administration & dosage / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D007150:Immunohistochemistry; D008111:Liver Function Tests; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D000077333:Telmisartan
D001562:Benzimidazoles; D001565:Benzoates; D020011:Protective Agents; D002216:Captopril; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000077333:Telmisartan; D008727:Methotrexate
Captopril; hepatotoxicity; methotrexate; telmisartan