STUDIES IN PORPHYRIA : I. A DEFECT IN THE REDUCTIVE TRANSFORMATION OF NATURAL STEROID HORMONES IN THE HEREDITARY LIVER DISEASE, ACUTE INTERMITTENT PORPHYRIA

A variety of 5β steroid metabolites derived from hormones natural to man are potent inducers experimentally of δ-aminolevulinate synthetase, the rate-limiting enzyme in porphyrin-heme formation. This mitochondrial enzyme is found at high levels of activity in the livers of patients with the genetic disease, acute intermittent porphyria (AIP). In this study the metabolism of (14)C-labeled testosterone was examined in AIP patients to determine whether there was a disproportionate conversion of the hormone to its 5β, compared to its 5α metabolite. The results indicate that AIP subjects do generate a substantially greater than normal fraction of 5β metabolite from this steroid; the excessive degree of ring A reduction of testosterone taking place via the 5β pathway in the porphyric patients averages 350% greater than in the nonporphyric subjects. In one asymptomatic AIP patient the disproportionate generation of 5β metabolite from the hormone reached a level 10 times the normal mean. Studies with a second (14)C-labeled hormone, dehydroisoandrosterone, whose metabolism in man resembles that of testosterone, confirmed the derangement in reductive transformation of steroids found in the individuals carrying the genetic lesion of AIP. These findings define a new endocrine abnormality in AIP patients and raise the possibility that endogenously derived 5β steroids may contribute by an induction mechanism to the increased levels of hepatic δ-aminolevulinate synthetase activity found in AIP patients.