ROLE OF METABOLISM IN THE ACTIVATION OF DEHYDROEPIANDROSTERONE AS A PEROXISOME PROLIFERATOR

The adrenal steroid dehydroepiandrosterone (DHEA) stimulates a dramati c increase in both the size and the number of peroxisomes present in l iver when given at pharmacological doses to rodents. Structurally dive rse chemicals including many fatty acids, hypolipidemic drugs and othe r foreign chemicals, can also induce such a peroxisome proliferative r esponse. This response is associated with a dramatic induction of pero xisomal fatty acid beta-oxidation enzymes and microsomal cytochrome P4 50 4A fatty acid hydroxylases and, long-term, can lead to induction of hepatocellular carcinoma. This review examines the underlying mechani sms by which DHEA induces peroxisome proliferation and evaluates the p ossible role of peroxisome proliferator-activated receptor (PPAR) in t his process. Like DHEA, the 17 beta-reduced metabolite 5-androstene-3 beta,17 beta-diol (ADIOL) is an active peroxisome proliferator when ad ministered in vivo, whereas androgenic and estrogenic metabolites of D HEA are inactive. In primary rat hepatocytes, however, DHEA and ADIOL are inactive as inducers of P450 4A and peroxisomal enzymes unless fir st metabolized by steroid sulfotransferase to the 3 beta-sulfates, DHE A-S and ADIOL-S. Investigations as to whether DHEA utilizes the same i nduction mechanism employed by classic, foreign chemical peroxisome pr oliferators, namely, activation of the intracellular receptor molecule PPAR, have shown that DHEA-S and ADIOL-S are ineffective with respect to PPAR activation in transient transfection/trans-activation assays. This inactivity of DHEA-S in vitro suggests a requirement for specifi c cellular transport or for further metabolism of the steroid which is only met in liver cells. Alternatively, the action of DHEA-S may requ ire accessory proteins or other nuclear factors that modulate the acti vity of PPAR, such as retinoid X receptor (RXR), hepatocyte nuclear fa ctor-4 (HNF-4) or chick ovalbumin upstream promoter transcription fact or (COUP-TF). Investigations using Ca2+-channel blockers such as nicar dipine suggest that there are important mechanistic similarities betwe en the foreign chemical- and DHEA-S-stimulated induction responses, an d support the hypothesis that these two classes of peroxisome prolifer ators both activate Ca2+-dependent signaling pathways. Further studies are required to ascertain whether this potential of DHEA and its sulf ated metabolites to serve as physiological modulators of fatty acid me tabolism and peroxisome enzyme expression contributes to the striking anticarcinogenic and other useful chemoprotective properties that DHEA is known to possess.