Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.3 (HSD)
 3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To better understand the molecular mechanisms of the pleiotropic responses induced by exposure to peroxisome proliferator chemicals (PPCs), we conducted a systematic search for genes whose mRNA levels are modulated by the PPC WY-14,643 (WY) in rat liver. The sequence of one up-regulated cDNA (2480 bp) was predicted to encode a protein of 735 aa with 82% identity to the porcine 17 beta-hydroxysteroid dehydrogenase type IV (HSD IV). Like the porcine enzyme, the rat HSD IV contains' a region homologous to yeast hydratase-dehydrogenase-epimerases and to sterol 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 (ACO) proteins in rat liver at different treatment times and concentrations of gemfibrozil and di-n-butyl phthalate were almost identical, indicating that HSD IV mRNA induction involves the peroxisome proliferator-activated receptor alpha, a regulator of ACO. 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 WY 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 ovulation.
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PMID:Rat 17 beta-hydroxysteroid dehydrogenase type IV is a novel peroxisome proliferator-inducible gene. 891 47

Exposure to some peroxisome proliferator chemicals (PPC) leads to toxic effects on sex organ function possibly by alterations of steroid hormone metabolism. A systematic search for genes whose mRNA levels are modulated by the PPC WY-14643 (WY) was carried out in rat liver, a site of steroid hormone metabolism. The sequence of one up-regulated cDNA (2480 bp) was predicted to encode a protein of 735 amino acids with 82% identity to the porcine 17 beta-hydroxysteroid dehydrogenase type IV (HSD IV) originally isolated as a 17 beta-estradiol dehydrogenase. The rat HSD IV was localized to peroxisomes and was regulated by diverse PPC by two distinct mechanisms. Induction of HSD IV and acyl-CoA oxidase (ACO) proteins in rat liver at different treatment times and concentrations of gemfibrozil (GEM) and di-n-butyl phthalate (DBP) were almost identical, suggesting that HSD IV mRNA induction involves the peroxisome proliferator-activated receptor alpha, a regulator of ACO. In contrast, HSD IV protein levels were only weakly induced by WY, a strong inducer of ACO protein, even though the levels of both HSD IV and ACO mRNA were strongly stimulated by WY. Thus HSD IV protein levels were uniquely regulated pretranslationally by WY. In addition to HSD IV we also identified the male-specific alpha 2u-globulin as a PPC down-regulated gene. This prompted us to examine the expression of another male-specific gene, CYP2C11, that catalyzes the hydroxylations of estradiol at the 2 and 16 alpha positions. Cyp2C11 protein expression in rat liver was either decreased or completely abolished after a 3-week treatment by GEM or WY, respectively. Decreased expression of enzymes which inactivate estradiol including Cyp2C11, and the reported increased expression of aromatase may explain why male rats exposed to diverse PPC have higher serum estradiol levels. These higher estradiol levels in male rats have been thought to be mechanistically linked to Leydig cell hyperplasia and adenomas. Increased conversion of estradiol to the less active estrone by HSD IV induction may explain how exposure to the phthalate di-(2-ethylhexyl) phthalate leads to decreases in serum estradiol levels and suppression of ovulation in female rats.
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PMID:Peroxisome proliferators alter the expression of estrogen-metabolizing enzymes. 920 13