Mouse strain-dependent hepatic interaction of psychoactive agents with ethanol and biogenic aldehydes metabolizing enzymes

The effect of multiple dose regimens of amantadine, reserpine, chlorpromazine alone or combined on liver alcohol (L-ADH) and aldehyde dehydrogenase (L-ALDH) was studied in three strains of mice. A strain-dependent difference between endogenous specific activity of these enzymes and their sensitivity to the agents studied was determined. The C57BL/6 mice showed most resistance to drug effect and possessed greater activity of mitochondrial L-ALDH isoenzymes and L-ADH than either ICR or BALB/C mouse strains, respectively. Amantadine induced both L-ADH and mitochondrial L-ALDH while reserpine inhibited them also as a function of mouse strain. Both reserpine-and chlorpromazine-mediated inhibition of albino ICR mouse L-ADH and BALB/C mitochondrial L-ALDH was alleviated by pretreatment with amantadine. This indicates antagonism between amantadine and these agents. The results suggest a genotypic sensitivity to drug action which may explain the individual sensitivity to the development of chlorpromazine and reserpine-produced side-effects, and the potency of amantadine in management of such drug-induced adverse reactions.