RAT 17-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-IV IS A NOVEL PEROXISOME PROLIFERATOR-INDUCIBLE GENE

To better understand the molecular mechanisms of the pleiotropic respo nses induced by exposure to peroxisome proliferator chemicals (PPCs), we conducted a systematic search for genes whose mRNA levels are modul ated by the PPC WY-14,643 (WY) in rat liver. The sequence of one up-re gulated cDNA (2480 bp) was predicted to encode a protein of 735 aa wit h 82% identity to the porcine 17 beta-hydroxysteroid dehydrogenase typ e IV (HSD IV). Like the porcine enzyme, the rat HSD IV contains a regi on homologous to yeast hydratase-dehydrogenase-epimerases and to stero l carrier proteins, indicating that the rat HSD IV has broad substrate specificity and contributes to cholesterol metabolism. The rat HSD IV was regulated by diverse PPCs via two distinct mechanisms. Induction of HSD IV and acyl-CoA oxidase (AGO) proteins in rat liver at differen t treatment times and concentrations of gemfibrozil and di-n-butyl pht halate were almost identical, indicating that HSD IV mRNA induction in volves the peroxisome proliferator-activated receptor alpha, a regulat or of AGO. In contrast, HSD IV protein levels were only weakly induced by WY, a strong inducer of ACO protein, even though the levels of HSD IV and ACO mRNA were strongly stimulated by WY and gemfibrozil. Thus, HSD IV protein levels were uniquely regulated pretranslationally by W Y via a novel mechanism. Increased conversion of estradiol to the less -active estrone by HSD IV induction may explain how phthalate exposure leads to decreases in serum estradiol levels and suppression of ovula tion.