Induction Of Drug-metabolizing Enzymes Research Articles

Ethanol metabolism in rats after microsomal metabolizing enzyme induction.

SummaryThe ability of a number of microsomal drug-metabolizing enzyme inducers to alter ethanol metabolism was examined. Phenobarbital, chlordane, chlorcyclizine, and 3-methylcholanthrene significantly increased drug metabolism as measured by a decrease in zoxazolamine paralysis time. Control rats metabolized ethanol at a rate of 44 mg/100 ml/hr and the rate was not altered when rats were treated with the various microsomal enzyme inducers. Therefore, it appears that agents which increase the miccrosomal metabolism of many drugs have little quantitative importance in determining the rate at which ethanol is metabolized by the rat.The author wishes to acknowledge the very able technical assistance of Mr. W. H. Whittley.

The effect of substituted phenols on liver weights and liver enzymes in the rat: Structure-activity relationships

The relative abilities of substituted phenols to induce drug-metabolizing enzymes were measured either 24 hr after a single dose or after 6–10 daily doses. The phenols carried various combinations of the substituents, methyl, ethyl, isopropyl, tert-butyl, tert-amyl, phenyl, benzyl, methoxy, methoxymethyl, hydroxymethyl, dimethylaminomethyl and nitro. When the effect was measured 24 hr after a single dose, a close relationship was found between the induction of drug-metabolizing enzymes and the lipid-water partition coefficient of the test compound. When the effect was measured after six daily doses this relationship was less distinct; further dosing could lead either to an accentuation or to a diminution of the effect.One compound which provided less evidence of induction after six doses than after a single dose was 2,6-di-tert-butyl-4-methoxymethylphenol. This regression of enzyme activity on repeated dosing was not related to any histological change or to the amount or distribution of histochemically-demonstrable glucose 6-phosphatase in the liver.Many of the substituted phenols also induced uridine diphosphate glucose dehydrogenase, an effect apparently unrelated either to the lipid-water partition coefficient or to the induction of drug-metabolizing enzymes.Liver enlargement was not invariably related to the induction of either drug-metabolizingactivities or uridine diphosphate glucose dehydrogenase.

Differences in the kinetics of benzpyrene hydroxylation by hepatic drug-metabolizing enzymes from phenobarbital and 3-methylcholanthrene-treated rats

o-Benzyl-p-chlorophenol (BCP) is widely used as a broad spectrum disinfectant. Treatment of male Fischer 344 rats with BCP resulted in an increase in cytochrome P-450 content and an accompanying decrease in aryl hydrocarbon hydroxylase (AHH) activity in both liver and kidney microsomes. Several other drug-metabolizing enzymes were not affected by BCP treatment. However, in kidney, BCP induced NADPH-cytochrome c reductase and uridine diphosphate glucuronyl transferase activities and caused a small increase in total cytochrome P-450 content and glutathione concentration. The cytochrome P-450 isozymes induced by BCP were fractionated by high pressure liquid chromatography (HPLC). The HPLC profile following BCP treatment most closely resembled that seen after phenobarbital. Using an immunoblotting procedure and a radioimmunoassay, it was shown that the increase in cytochrome P-450 content in the liver after BCP treatment was, in part, due to an increase in the phenobarbital-inducible isozymes, P-450b + e. In the kidney, the increase in total cytochrome P-450 content after BCP exposure was not due to an increase in P-450b + e. The decrease in AHH activity appeared to be caused by noncompetitive inhibition of constitutive AHH activity by BCP. BCP also inhibited benzphetamine demethylation, although to a lesser extent. The failure to observe an increase in benzphetamine demethylase activity in vivo, despite the induction of P-450b, was probably due to the concomitant induction and inhibition of drug-metabolizing enzymes by BCP.

Erratum: Induction of Drug-Metabolizing Enzymes in Liver Microsomes of Mice and Rats by Softwood Bedding

In the report "Induction of drug-metabolizing enzymes in liver microsomes of mice and rats by softwood bedding" by Elliot S. Vesell (1 Sept., p. 1057), the last sentence in the table head (Table 1) should read "All differences are significant ( P < .01)."

Induction of Drug-Metabolizing Enzymes in Liver Microsomes of Mice and Rats by Softwood Bedding

Induction of Drug-Metabolizing Enzymes in Liver Microsomes of Mice and Rats by Softwood Bedding

Induction of Drug-Metabolizing Enzymes in Liver Microsomes of Mice and Rats by Softwood Bedding

Induction of three drug-metabolizing enzymes occurred in liver microsomes of mice and rats kept on softwood bedding of either red cedar, white pine, or ponderosa pine. This induction was reversed when animals were placed on hardwood bedding composed of a mixture of beech, birch, and maple. Differences in the capacity of various beddings to induce may partially explain divergent results of studies on drug-metabolizing enzymes. The presence of such inducing substances in the environment may influence the pharmacologic responsiveness of animals to a wide variety of drugs.

Analysis and differentiation of the mechanism in the development of drug tolerance.

Repeated administration of many drugs, especially central acting drugs, cause a development of tolerance to same or related drugs. The development of drug tolerance is an important problem for the evalution of drug actions and for the determination of a schedule of drug administration. However, the mechanism of development of drug tolerance is still in obscure. On the other hand, it is recently well demonstrated by several investigators that single or repeated administration of various drugs induces an increase in the activities of drug-metabolizing enzymes of liver microsomes (1-4). Thus, the actions of the same drugs or other drugs given successively are markedly decreased through the increased rates of drug metabolisms (2, 4, 5). It has been well known that most of the central acting drugs are the inducers of drug-metabolizing enzymes of liver microsomes (2, 4, 5). The purpose of present communication, therefore, is to analyse and differentiate the mechanism of the development of drug tolerance. The results of the present investigation showed that there are two kind of drug tolerances and the first one would be called as apparent tolerance and the second one would be called as real tolerance. The development of the first one is mainely due to the induction of drug-metabolizing enzymes of liver microsomes and the second one is mainely due to the decreased tissue sensitivity to the drug. A simple and effective method to differentiate the two kinds of drug tolerance is the joint injection of inhibitors of enzyme protein synthesis, such as ethionine, with the designed drugs.

Lack of chronic morphine effect on the induction of drug-metabolizing enzymes of liver microsomes by phenobarbital in female rats.

Lack of chronic morphine effect on the induction of drug-metabolizing enzymes of liver microsomes by phenobarbital in female rats.

Factors affecting the toxicity and metabolism of OMPA (octamethylpyrophosphoramide) in rats.

Octamethylpyrophosphoramide (OMPA) is a potent inhibitor of cholinesterase in vivo. However, OMPA itself is a very weak inhibitor, but it is converted to a potent inhibitor following oxidation by liver microsomes (1-4). In a pervious paper it is reported that the administration of thiopental or phenaglycodol markedly increased the toxicity of OMPA in female rats (5). Since the joint administration of ethionine with thiopental or phenaglycodol completely blocked the effect of thiopental or phenaglycodol, it was postulated that the induction of microsomal enzyme which activates the metabolism of OMPA was involved in the increased toxicity after thiopental or phenaglycodol treatment. In the present investigation, the effect of phenobarbital and methylcholanthrene on the toxicity and metabolism of OMPA in female and male rats were studied to confirm this postulation. Phenobarbital and methylcholanthrene are well known inducers of drug-metabolizing enzymes of liver microsomes (6-8). However, the administration of both drugs likely give different effects on the microsomal enzymes (9-11). The typical difference were also evidenced in the present works. In addition the marked sex difference was observed on the metabolism of many drugs by liver microsomes, and the metabolism of OMPA in male rats was much faster than that in female rats (2, 12-16). In the present studies the marked sex difference was also observed in the effect of phenobarbital and methylcholanthrene on the metabolism and toxictity of OMPA. These results may offer a typical example for the role of the metabolism of drugs by liver microsomes for the determination of drug toxicity.

Enhanced phenobarbital induction of liver microsomal drug-metabolizing enzymes in mice infected with murine hepatitus virus

The effect of an infection in mice with a murin hepatitis virus Buescher type (MHVB) on the liver microsomal drug metabolizing enzymes is investigated, alone, as well as in combination with phenobarbital pretreatment. A diphasic effect of the infection with MHVB on the microsomal drug-metabolizing enzymes is observed: the enzyme activity is slightly increased 12 hr after the infection and is markedly depressed 48–60 hr after. The effect of phenobarbital pretreatment on the microsomal drug metabolizing enzymes is markedly enhanced in mice infected 12 or 24 hr previously. These results suggest that the condition of stimulated biosynthesis of protein and RNA in the liver of infected mice may enhance the effect of phenobarbital.

150 Factors influencing induction of microsomal drug-metabolizing enzymes of liver

150 Factors influencing induction of microsomal drug-metabolizing enzymes of liver