STUDIES IN PORPHYRIA

Abstract

Patients with the genetic liver disease, acute intermittent porphyria (AIP), have a defect in the reductive transformation of steroid hormones that is manifest by the disproportionate generation of 5ß-steroid metabolites from precursor hormones. 5ß-steroid metabolites were earlier shown to be potent inducers experimentally of δ-aminolevulinate synthetase (ALAS), the mitochondrial enzyme that is rate-limiting in porphyrin synthesis, and that is found at high levels of activity in the livers of AIP patients. In this report, the basis for the defective steroid metabolism in AIP has been shown, through studies with the 14C-labeled adrenal hormone 11ß-hydroxy-Δ4-androstenedione, to reside in a substantial deficiency of hepatic steroid Δ4-5α-reductase activity. This enzymic deficiency was found in all seven AIP patients studied, and ranged from 34% to as much as 70% below the mean enzyme activity characterizing normal subjects. The functional consequence of the low levels of 5α-reductase activity in AIP is to divert the reductive transformation of certain natural hormones from the 5α- to the 5ß-pathway; the latter is the metabolic route through which endogenous steroids having the potential for inducing hepatic ALAS are generated. It is not presently known whether the 5α-reductase deficiency in AIP is acquired in some fashion or whether it has partial genetic determinants. It seems probable, however, that this enzymatic abnormality, coupled with the dramatic increase in hormone synthesis that occurs at puberty, may be of major importance in determining clinical expression of the latent gene defect for AIP in many individuals. The 5α-reductases for steroid hormones are known to be localized in the endoplasmic reticulum of hepatic cells and the present findings in AIP thus represent the first demonstration that an enzymic component of these membranous structures is functionally abnormal in this hereditary liver disease.