Genetic predisposition to drug hepatotoxicity: role in hepatitis caused by amineptine, a tricyclic antidepressant.
Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathione concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.
Larrey
D
D
Unité de Recherches de Physiopathologie Hépatique (INSERM U24), Hôpital Beaujon, Clichy, France.
Berson
A
A
Habersetzer
F
F
Tinel
M
M
Castot
A
A
Babany
G
G
Lettéron
P
P
Freneaux
E
E
Loeper
J
J
Dansette
P
P
D000293:Adolescent; D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects* / Q000633:toxicity; D002470:Cell Survival; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D003915:Dextromethorphan / Q000652:urine; D003917:Dextrorphan / Q000652:urine; D003986:Dibenzocycloheptenes / Q000009:adverse effects* / Q000633:toxicity; D005192:Family Health; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010641:Phenotype
D000929:Antidepressive Agents, Tricyclic; D003986:Dibenzocycloheptenes; D003917:Dextrorphan; C011597:amineptin; D003915:Dextromethorphan