Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation

Background/Aims: Although sublingual buprenorphine is safely used as a subs titution drug in heroin addicts, large overdoses or intravenous misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3 A. Methods: We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and it s toxicity in isolated rat hepatocytes and treated mice. Results: Whereas norbuprenorphine had few mitochondrial effects, buprenorph ine (25-200 muM) concentrated in mitochondria, collapsed the membrane poten tial, inhibited beta -oxidation, and both uncoupled and inhibited respirati on in rat liver mitochondria, Both buprenorphine and norbuprenorphine (200 muM) underwent CYP3A-mediated covalent binding to rat liver microsomal prot eins and both caused moderate glutathione depletion and increased cell calc ium in isolated rat hepatocytes, but only buprenorphine also depleted cell adenosine triphosphate (ATP) and caused necrotic cell death. Four hours aft er buprenorphine administration to mice (100 nmol/g body weight), hepatic g lutathione was unchanged, while ATP was decreased and serum transaminase in creased. This transaminase increase was attenuated by a CYP3A inducer and a ggravated by a CYP3A inhibitor. Conclusions: Both buprenorphine and norbuprenorphine undergo metabolic acti vation, but only buprenorphine impairs mitochondrial respiration and ATP fo rmation. The hepatotoxicity of high concentrations or doses of buprenorphin e is mainly related to its mitochondrial effects. (C) 2001 European Associa tion for the Study of the Liver. Published by Elsevier Science B.V. All rig hts reserved.