Hepatic Microsomal Drug-metabolizing Enzymes Research Articles

The Effect of Actinomycin D on Post-phenobarbital Activity of Hepatic Microsomal Drug-metabolizing Enzymes in the Rat

Abstract Administration of actinomycin D to rats, 24 hours after phenobarbital pretreatment, did not sustain or enhance the phenobarbital-induced increased activity of two hepatic microsomal drug-metabolizing enzymes. This was true whether the phenobarbital was given as a single dose or as multiple doses and at either of two doses of actinomycin D. No evidence for a repressor of hepatic microsomal drug-metabolizing enzymes was obtained in these studies.

Effects of 3,4-benzpyrene, phenobarbital, and chlordane on the nucleic acid and protein content of subfractions of rat liver homogenates

3,4-Benzpyrene, phenobarbital, and chlordane are three compounds that produce marked increases in the activities of hepatic microsomal drug-metabolizing enzyme systems. They were compared with regard to their effects on the nucleic acid and protein content of various subfractions of rat liver homogenates. Pretreatment of rats with chlordane and phenobarbital produced similar changes. The changes produced by pretreatment with 3,4-benzpyrene, however, differed from those of phenobarbital and chlordane. The differences between the effects of 3,4-benzpyrene and those of chlordane and phenobarbital were noted primarily in the subfractions of rat liver homogenates which contained largely smooth endoplasmic reticulum (SER). Chlordane and pheno-barbital caused significantly greater increases than 3,4-benzpyrene in the RNA and protein content of the fraction containing the SER. Pretreatment with each of the three compounds produced statistically significant decreases in DNA content of liver homogenates when expressed as mg DNA/g liver. Considered in the light of previously accumulated evidence, the results provided further support for the hypothesis that 3,4-benzpyrene may exert its stimulatory effects on hepatic microsomal drug-metabolizing enzyme systems through a mechanism different from that of phenobarbital and chlordane.

Stimulation of Hepatic Microsomal Drug-Metabolizing Enzyme Systems in Primates by DDT

Stimulation of Hepatic Microsomal Drug-Metabolizing Enzyme Systems in Primates by DDT

The effect of chronic phenobarbital administration on some hepatic drug-metabolizing enzyme activities in the rat

Prolonged administration of phenobarbital produces an increase in hepatic microsomal drug-metabolizing enzyme activity in some animals. Burns and Conney 1 gave phenobarbital to dogs for 2 months and found enhanced metabolism of phenylbutazone for as long as 6 weeks after cessation of therapy. In a similar study, Remmer et al. 2,3 noted that canine microsomal enzyme activity, with hexobarbital and aminopyrine as substrates, remained elevated for 2 to 4 months after stopping a 2–3-month course of phenobarbital treatment. A single overdose of hypnotics in man can enhance 4-aminoantipyrine production from Novalgin for as long as 15 days. 2 The activity of microsomal drug-metabolizing enzymes in rat liver during and after chronic phenobarbital administration has not been studied. Using rats, Orrenius and Ernster 4 have shown that formation of formaldehyde from aminopyrine falls to control levels within 6 days after short-term administration of phenobarbital (every day for 5 days). In view of this, four microsomal drug-metabolizing pathways were measured in livers from rats given phenobarbital for varying periods of time up to 2 months. A plateau in rate of hexobarbital metabolism was reached during the treatment with phenobarbital, and a rapid decline in enzyme activity was observed after stopping this treatment.

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

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.