Effects of norethynodrel and progesterone on hepatic microsomal drug-metabolizing enzyme systems

Abstract

Two progestational steroids, norethynodrel and progesterone, have been compared in their effects on hepatic drug-metabolizing enzyme systems in vitro. The steroids were added directly to incubation mixtures containing 9000 g supernatant fractions of rat liver homogenates, appropriate cofactors, and drug substrates. Norethynodrel and progesterone at 10 −5 and 10 −4 M concentrations markedly inhibited the side-chain oxidation of hexobarbital, ring hydroxylation of zoxazolamine, and p-hydroxylation of aniline. To a lesser degree they also inhibited the ring hydroxylation of 3,4-benzpyrene and the N-demethylation of aminopyrine. They did not appreciably affect the reduction of the nitro radical of p-nitrobenzoic acid, the reduction of the azo linkage of neoprontosil, the o-demethylation of codeine, or the metabolism of chlorpromazine. When animals were pretreated with these steroids, only the metabolisms of zoxazolamine and hexobarbital were affected in vitro. Both agents were capable of inhibiting the metabolism in vitro of these drug substrates when administered 1 or 2 hr prior to sacrifice of the animals. Norethynodrel stimulated the metabolism of hexobarbital when administered between 18 and 48 hr before sacrifice. Hexobarbital metabolism was also stimulated after subacute (daily for 3 days) and chronic (daily for 3 weeks) pretreatment with norethynodrel. Pretreatment with norethynodrel produced a stimulation of zoxazolamine metabolism when administered between 18 and 36 hr prior to sacrifice of the animals. Stimulation was also observed after chronic administration of norethynodrel. Pretreatment with progesterone produced no stimulation of hexobarbital or zoxazolamine metabolism.