RAT CYP3A and CYP2B1/2 were not associated with nevirapine-induced hepatotoxicity.
Nevirapine is an antiretroviral drug that is used for treatment as well as for the prevention of mother-to-child transmission of the human immunodeficiency virus (HIV). Unfortunately, its adverse effects, mainly hypersensitivity skin reactions and hepatotoxicity, have hampered the use of nevirapine. Since nevirapine-induced hepatotoxicity commonly occurs between 2-12 weeks of treatment, and nevirapine is a known inducer of human CYP3A and CYP2B6 isozymes, it was envisaged that the hepatotoxicity was due to activation of nevirapine to toxic metabolites by the induced enzymes. Therefore, the aim of this study was to use a rat model and determine the role of the rat analogues, rat CYP3A and CYP2B1/2, in nevirapine-induced hepatotoxicity. This was tested by the extent at which hepatotoxicity could be prevented when ketoconazole or thiotepa, known inhibitors of CYP3A and CYP2B1/2, respectively, were given one hour prior to administration of a hepatotoxic dose of nevirapine. It was shown here that nevirapine-induced hepatotoxicity only occurred in animals that were pretreated with an enzyme inducer (dexamethasone or nevirapine); that ketoconazole and thiotepa did not prevent the occurrence of nevirapine-induced hepatotoxicity; and that histopathologic examinations were more accurate than the use of liver enzymes in detecting the liver damage. This suggested that nevirapine-induced hepatotoxicity is closely associated with enzyme induction, and that liver function tests alone might not be good markers for determining nevirapine-induced hepatotoxicity. In conclusion, rat CYP3A and CYP2B1/2 may not be involved in the pathogenesis of nevirapine-induced hepatotoxicity, suggesting that a different enzyme inducible by nevirapine or dexamethasone may be responsible. However, this is yet to be proven in humans.
Walubo
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The Department of Pharmacology, University of the Free State, Bloemfontein, South Africa. waluboa.md@mail.uovs.ac.za
Barr
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Abraham
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AM
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007441:Intubation, Gastrointestinal; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008111:Liver Function Tests / Q000379:methods; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013852:Thiotepa / Q000494:pharmacology; D013997:Time Factors
D019380:Anti-HIV Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; C004180:dexamethasone 21-phosphate; D003907:Dexamethasone; D013852:Thiotepa; D019829:Nevirapine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007654:Ketoconazole