The hepatic enzymes that catalyze drug oxidations and the redtuctive metabolism of steroid hormones to 5a-derivatives are localized in membranes of the endoplasmic reticulum. Phenobarbital, whiclh exacerbates acute intermittent porphyria in mnan, induices drug-oxidizing enzymes in liver. Additionally, patients in whom the primary gene defect (uiroporphyrinogen-I-synthetase deficiency) of actute intermittent porphyria has become clinically expressed have low levels of hepatic steroid A4-5a-reductase activity. This 5a-reductase deficiency in actute intermittent porphyria leads to the disproportionate generation of 5/3-steroid metabolites from prectursor hormones; such steroid metabolites have significant porphyria-inducing action experimentally. In tlhis study the effects of phenobarbital on drug oxidation and steroid 5a-reduction in man were examined to determine if this drtug could produice changes in steroid 5a-reductase activity which mimicked those seen in patients with acute intermittent porphyria. mimicks the high 5/8/5a-steroid metabolite ratio formed from endogenotis hormones in acute intermittent porphyria. The proximate mechanism by which phenobarbital indtuces reciprocal changes in activities of the microsomal enzymes which catalyze drtug oxidations and steroid 5a-redtictions is not known. This action of phenobarbital raises the possibility, however, that certain drugs which provoke exacerbations of htuman porphyria may do so, in part, by produicing deleteriouis shifts in the patterns of endogenouis steroid hormone metabolism.