PHARMACOLOGICAL IMPLICATIONS OF MICROSOMAL ENZYME INDUCTION
Authors: A.H. CONNEY
Journal: Pharmacological Reviews (1967)

In increasingly large numbers, drugs, pesticides, herbicides, food additives, and environmental carcinogenic hydrocarbons are being found to stimulate their own metabolism or the metabolism of other compounds. The evidence suggests that foreign chemicals exert this action by increasing the amount of drug-metabolizing enzymes in liver microsomes.Treatment of animals or man with suitable inducers of liver microsomal enzymes accelerates drug metabolism in vivo and alters the duration and intensity of drug action. For instance, barbiturates decrease the anticoagulant activity of coumarin anticoagulants by accelerating their metabolism. This effect requires that the dosage of coumarins be raised to obtain an adequate anticoagulant response, and serious toxicity can result after combined therapy with a coumarin anticoagulant and a stimulator of drug metabolism when the enzyme stimulator is withdrawn and the anticoagulant is continued without an appropriate decrease in dose.

The stimulatory effect of drugs on their own metabolism often allows the organism to detoxify drugs more rapidly. This effect has considerable importance when it causes drugs to become less toxic and less effective during prolonged administration. However, if a metabolite has more activity than the parent drug, enzyme induction can enhance the drug's action. Enzyme induction may also be important during chronic exposure to environmental carcinogens, such as 3, 4-benzpyrene. The ability of 3, 4-benzpyrene to stimulate its own metabolism in liver, lung, gastrointestinal tract and skin represents an important mechanism for the detoxification of this substance.

Inducers of microsomal enzymes stimulate the metabolism or synthesis of several normal body substrates such as steroid hormones, pyridine nucleotides, cytochromes, and bilirubin. Evidence has accumulated that steroids are normal body substrates of drug-metabolizing enzymes in liver microsomes. Accordingly, treatment of rats with phenobarbital enhances the hydroxylation of androgens, estrogens, glucocorticoids, and progestational steroids by liver microsomes. This effect is paralleled in vivo by enhanced metabolism of steroids to polar metabolites and by a decreased action of steroids such as estradiol, estrone, and progesterone.

Recent studies suggest that inducers of liver microsomal enzymes enhance the hydroxylation of steroids in man. Phenobarbital, diphenylhydantoin, and phenylbutazone are examples of drugs that stimulate cortisol hydroxylase activity in guinea pig liver microsomes and enhance the urinary excretion of 6 β-hydroxycortisol in man. Further research is needed to learn whether the stimulatory action of drugs on the metabolism of normal body constituents is harmful or whether it restores a homeostasis that was upset by drug administration. It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for the treatment of Cushing's syndrome. Considerable further work is required to evaluate more completely the effects of liver microsomal enzyme inducers on the metabolism of bilirubin, cortisol, and other normal body constituents in experimental animals and man.