Metabolic activation of the tricyclic antidepressant amineptine--II. Protective role of glutathione against in vitro and in vivo covalent binding.
Incubation of [11-14C]amineptine (1 mM) with an NADPH-generating system and hamster liver microsomes resulted in the in vitro covalent binding of an amineptine metabolite to microsomal proteins; this binding was decreased by 41-71% in the presence of cysteine, lysine, glycine or glutathione (0.5 mM). An inverse relationship was found between the concentration of glutathione in the incubation mixture (0.25-4 mM) and the extent of covalent binding in vitro, which became undetectable at concentrations of glutathione of 2 mM and higher. Administration of [11-14C]amineptine (300 mg/kg-1 i.p.) to hamsters pretreated with phorone (500 mg/kg i.p.) resulted in the in vivo covalent binding of an amineptine metabolite to hepatic proteins. This binding was increased by phenobarbital-pretreatment and decreased by piperonyl butoxide-pretreatment. After various doses of phorone (150-500 mg/kg), an inverse relationship was found between hepatic glutathione content and in vivo covalent binding. Administration of amineptine alone (300 mg/kg i.p.) depleted hepatic glutathione by 16% only; in these animals, in vivo covalent binding was undetectable from background. Amineptine (300 mg/kg i.p.) did not produce hepatic necrosis, even in hamsters pretreated with phorone and/or phenobarbital. We conclude that physiologic concentrations of glutathione essentially prevent the in vivo covalent binding of an amineptine metabolite to hepatic proteins, and that this binding does not produce liver cell necrosis in hamsters.
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism*; D001711:Biotransformation; D019328:Buthionine Sulfoximine; D006224:Cricetinae; D003986:Dibenzocycloheptenes / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008647:Mesocricetus; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D003986:Dibenzocycloheptenes; D007659:Ketones; D008717:Methionine Sulfoximine; C011597:amineptin; D019328:Buthionine Sulfoximine; D009249:NADP; C018637:phorone; D005978:Glutathione; D010882:Piperonyl Butoxide; D010634:Phenobarbital