PROTECTIVE EFFECTS OF NIFEDIPINE, VERAPAMIL AND DILTIAZEM AGAINST ACUTE ACETAMINOPHEN HEPATOTOXICITY IN ADULT MALE ALBINO RATS

Acetaminophen is one of the commonly prescribed over the-counter analgesic and antipyretic medications (Flaherty, 1998 and Abbott and Fraser, 1998). It is relatively safe and effective at therapeutic doses, but high doses of the drug cause fulminant liver necrosis in human and experimental animals (Matthews et aI., 1996). Hepatotoxicity is thought to resultfrom the cytochrome P450~mediated oxidation of acetaminophen to Nacetyl- p-benzoquinone imine (NAPQI) which is highly reactive and is considered the toxic metabolite of acetaminophen (Harman et aI., 1991). This highly reactive metabolite is scavenged by reduced glutathione (GSH), leading to a decrease of hepatic GSH concentration after acetaminophen (Anundi et al., 1993). Depletion of GSH causes the remaining quinone to bind to cellular macromolecules leading to cell death by a cellular oxidative stress resulting in lipid peroxidation and changes in intracellular Ca2+ homeostasis (Cohen and Khairallah, 1997).