Induction of peroxisomal beta-oxidation by structural analogues of dehydroepiandrosterone in cultured rat hepatocytes: structure-activity relationships.
The structural requirements of dehydroepiandrosterone (DHEA) for the induction of peroxisomal beta-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 beta-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 beta-oxidation and 5.1- to 10.9-fold for carnitine acetyltransferase at 50 microM. 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 beta-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 (beta-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 beta-oxidation, suggesting the presence of a certain specific recognition site in the cell for DHEAS, which mediates the peroxisome proliferator action of DHEA.
Sakuma
M
M
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Japan.
Yamada
J
J
Suga
T
T
D000818:Animals; D002332:Carnitine O-Acetyltransferase / Q000096:biosynthesis; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate; D004790:Enzyme Induction; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D002332:Carnitine O-Acetyltransferase