I. A DEFECT IN THE REDUCTIVE TRANSFORMATION OF NATURAL STEROID HORMONES IN THE HEREDITARY LIVER DISEASE, ACUTE INTERMITTENT PORPtIYRIA*

The hereditary liver disease, acute intermittent porphyria (ALP), 1 is characterized clinically by a disabling, sometimes lethal, neurological-visceral symptom complex and biochemically by excessive activity of the porphyrin-heme biosynthetic pathway (1-3). The mitochondrial enzyme 6-aminolevulinate synthetase (ALAS), which is rate limiting for this pathway (4), is found at high levels of activity in the livers of AIP patients (5, 6), and this accounts for the excessive formation and subsequent excretion into the urine of porphyrin precursors which characterizes the disorder. The high levels of hepatic ALAS in AIP have been postulated to reflect an operator gene defect (5, 7, 8) which ultimately finds expression in the "over-production" of this enzyme. ALAS is, however, readily inducible in the liver by a variety of drugs and foreign chemicals (9-11), and recent studies from these laboratories have demonstrated that many 5/3 steroid metabolites derived from hormones natural to man are also potent inducers of this enzyme (12-14). The occurrence of this endogenous class of potent inducers of ALAS raised the possibility that AIP patients might have abnormalities in steroid hormone biotransformation which lead to the disproportionate formation of 5/3 metabolites from precursor compounds. If so, such steroids could contribute by an induction mechanism to the high levels of hepatic ALAS activity which characterize AIP patients.