Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation.
OBJECTIVE
Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large overdoses or intravenous misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3A.


METHODS
We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and its toxicity in isolated rat hepatocytes and treated mice.


RESULTS
Whereas norbuprenorphine had few mitochondrial effects, buprenorphine (25-200 microM) concentrated in mitochondria, collapsed the membrane potential, inhibited beta-oxidation, and both uncoupled and inhibited respiration in rat liver mitochondria. Both buprenorphine and norbuprenorphine (200 microM) underwent CYP3A-mediated covalent binding to rat liver microsomal proteins and both caused moderate glutathione depletion and increased cell calcium in isolated rat hepatocytes, but only buprenorphine also depleted cell adenosine triphosphate (ATP) and caused necrotic cell death. Four hours after buprenorphine administration to mice (100 nmol/g body weight), hepatic glutathione was unchanged, while ATP was decreased and serum transaminase increased. This transaminase increase was attenuated by a CYP3A inducer and aggravated by a CYP3A inhibitor.


CONCLUSIONS
Both buprenorphine and norbuprenorphine undergo metabolic activation, but only buprenorphine impairs mitochondrial respiration and ATP formation. The hepatotoxicity of high concentrations or doses of buprenorphine is mainly related to its mitochondrial effects.
INSERM U481 and Centre de Recherche sur les Hépatites Virales de l'Association Claude Bernard, H pital Beaujon, Clichy, France.
A
A
Berson
D
D
Fau
R
R
Fornacciari
P
P
Degove-Goddard
A
A
Sutton
V
V
Descatoire
D
D
Haouzi
P
P
Lettéron
A
A
Moreau
G
G
Feldmann
D
D
Pessayre
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000478:Alkylation; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002047:Buprenorphine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009294:Narcotics / Q000493:pharmacokinetics* / Q000633:toxicity*; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014475:Uncoupling Agents / Q000494:pharmacology
D009294:Narcotics; D014475:Uncoupling Agents; D002047:Buprenorphine; C043585:norbuprenorphine; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating