Induction of peroxisomal β-oxidation by structural analogues of dehydroepiandrosterone in cultured rat hepatocytes: Structure-activity relationships

Abstract

The structural requirements of dehydroepiandrosterone (DHEA) for the induction of peroxisomal β-oxidation were studied in cultured rat hepatocytes. The hepatocytes were incubated for 5 days with various steroids, including 3- and 17-substituted analogues and 5-hydrogenated analogues of DHEA, and the activities of peroxisomal β-oxidation and carnitine acetyltransferase were measured. Among the steroids examined, DHEA, DHEA sulfate (DHEAS), dehydroandrosterone sulfate, androstenediol 3-sulfate, epiandrosterone sulfate and androsterone sulfate significantly induced the enzymes; 4.6- to 14.2-fold for β-oxidation and 5.1- to 10.9-fold for carnitine acetyltransferase at 50 μM. All of the sulfated steroids were more effective 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. Furthermore, the relatively planar conformation of the steroidal hydrophobic backbone was crucial for inducing the enzyme. The configuration of the 3-sulfuric group (β-configuration) and the presence of a double bond at position C5 were not primary determinants for the action of DHEAS. On the other hand, the introduction of bulky substituents to position C17 or aromatization of ring A led to a loss of inducing activity. Thus, there are strict structural requirements for the DHEA induction of peroxisomal β-oxidation, suggesting the presence of a certain specific recognition site in the cell for DHEAS, which mediates the peroxisome proliferator action of DHEA.