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Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

Okwa IB, Akindele AJ, Agbaje EO, Oshinuga OT, Anunobi CC, Adeyemi OO - EXCLI J (2013)

Bottom Line: The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test.These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA).The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, P.M.B. 12003, Lagos, Nigeria.

ABSTRACT
Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

No MeSH data available.


Related in: MedlinePlus

Effect of nifedipine, verapamil and diltiazem on in vivo antioxidant indices in liver samples in zidovudine-induced hepatotoxicity in rats
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T6: Effect of nifedipine, verapamil and diltiazem on in vivo antioxidant indices in liver samples in zidovudine-induced hepatotoxicity in rats

Mentions: Zidovudine (800 mg/kg, p.o.) caused significant (P < 0.01) reductions in the levels of GSH, SOD, CAT, GPx and total protein in liver samples but the level of MDA was significantly (P < 0.001) increased compared to control (Table 6(Tab. 6)). Silymarin (50 mg/kg, p.o.) significantly (P < 0.05, 0.01, 0.001) reversed the effect of zidovudine on these parameters especially as it relates to GSH, CAT and MDA. Nifedipine at the subclinical dose (0.17 mg/kg, p.o.), clinical dose (0.86 mg/kg, p.o.) and supraclinical dose (4.23 mg/kg, p.o.) reversed the elevation in the levels of MDA produced by zidovudine, with peak protective effect observed at the clinical dose. However, the level of CAT observed with nifedipine at the clinical and supraclinical doses were significantly (P < 0.05, 0.01) lower when compared with the zidovudine only treated rats. Verapamil at all doses (subclinical, 0.86 mg/ kg; clinical, 4.29 mg/kg; and supraclinical, 21.43 mg/kg, p.o.) significantly (P < 0.01, 0.001) reversed the elevation of MDA level produced by zidovudine. Verapamil also significantly (P< 0.05) increased the levels of SOD at the clinical dose but there was a significant (P < 0.01) reduction in CAT level at the supraclinical dose compared to zidovudine. Diltiazem at the supraclinical dose (4.23 mg/kg, p.o.) significantly (P < 0.05, 0.01) increased zidovudine diminished level of GSH, with a reversal of the increased level of MDA observed with zidovudine (Table 6(Tab. 6)).


Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

Okwa IB, Akindele AJ, Agbaje EO, Oshinuga OT, Anunobi CC, Adeyemi OO - EXCLI J (2013)

Effect of nifedipine, verapamil and diltiazem on in vivo antioxidant indices in liver samples in zidovudine-induced hepatotoxicity in rats
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4552102&req=5

T6: Effect of nifedipine, verapamil and diltiazem on in vivo antioxidant indices in liver samples in zidovudine-induced hepatotoxicity in rats
Mentions: Zidovudine (800 mg/kg, p.o.) caused significant (P < 0.01) reductions in the levels of GSH, SOD, CAT, GPx and total protein in liver samples but the level of MDA was significantly (P < 0.001) increased compared to control (Table 6(Tab. 6)). Silymarin (50 mg/kg, p.o.) significantly (P < 0.05, 0.01, 0.001) reversed the effect of zidovudine on these parameters especially as it relates to GSH, CAT and MDA. Nifedipine at the subclinical dose (0.17 mg/kg, p.o.), clinical dose (0.86 mg/kg, p.o.) and supraclinical dose (4.23 mg/kg, p.o.) reversed the elevation in the levels of MDA produced by zidovudine, with peak protective effect observed at the clinical dose. However, the level of CAT observed with nifedipine at the clinical and supraclinical doses were significantly (P < 0.05, 0.01) lower when compared with the zidovudine only treated rats. Verapamil at all doses (subclinical, 0.86 mg/ kg; clinical, 4.29 mg/kg; and supraclinical, 21.43 mg/kg, p.o.) significantly (P < 0.01, 0.001) reversed the elevation of MDA level produced by zidovudine. Verapamil also significantly (P< 0.05) increased the levels of SOD at the clinical dose but there was a significant (P < 0.01) reduction in CAT level at the supraclinical dose compared to zidovudine. Diltiazem at the supraclinical dose (4.23 mg/kg, p.o.) significantly (P < 0.05, 0.01) increased zidovudine diminished level of GSH, with a reversal of the increased level of MDA observed with zidovudine (Table 6(Tab. 6)).

Bottom Line: The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test.These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA).The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, P.M.B. 12003, Lagos, Nigeria.

ABSTRACT
Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

No MeSH data available.


Related in: MedlinePlus