INDUCTION OF PEROXISOMAL β-OXIDATION ENZYMES BY DEHYDROEPIANDROSTERONE SULFATE

Abstract

Induction of peroxisomal β-oxidation enzymes by dehydroepiandrosterone (DHEA) was studied in primary cultures of rat hepatocytes. Treatment of cultured hepatocytes with DHEA and its sulfate (DHEAS) for up to 5 days resulted in a progress increase in peroxisomal β-oxidation and camitine acetyltransferase activity, the magnitude of which was dose-related. Western blot analyses confirmed the induction of acyl-CoA oxidase, enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme and carnitine acetyltransferase in the treated cells. Induction of fatty acid ω-hydroxylase proteins (P4504As) was also revealed. DHEAS was a good inducer of these enzymes, and its effects coorelated well with those of DHEA; moreover, DHEAS was more potent than DHEA. Studies with structural analogues of DHEA revealed strict structural requirements for DHEA induction of peroxisomal β-oxidation. Of the steroids examined, dehydroandrosterone sulfate, androstenediol 3-sulfate, epiandrosterone sulfate and androsterone sulfate, besides DHEA and DHEAS, significantly induced the enzyme. All of the sulfated steroids were more potent than the corresponding unsulfated forms. DHEAS was the most potent inducer. The 3-sulfuric group was required for the marked induction of peroxisomal β-oxidation, and the 17-carbonyl group was also important. The presence of a double bond at position C5 was not a primary determinant for the action of DHEAS, but the relatively planar conformation of the steroidal hydrophobic backbone was crucial for inducing the enzyme. Certain metabolites, such as 16a-hydroxyDHEA, androstenedione and DHEA glucuronide, also caused enzyme induction, however the magnitude of which was lower than that seen with DHEA and DHEAS. When hepatocytes were co-treated with acetaminophen, a potent sulfate scavenger, or chlorate, an inhibitor of PAPS formation, the DHEA induction of peroxisomal β-oxidatiown as suppressed, whereas induction by DHEAS and clofibric acid was not affected. These findings support the idea that DHEA, after administration, undergoes sulfate-conjugation in the cell to gain peroxisome proliferator activity.