title: Testosterone-metabolizing capacity and characteristics of adrenal microsomes in human fetus in vitro.
abstract: We describe the metabolite spectrum of testosterone (T) in human fetal adrenal in vitro, and verify possible roles of CYP3A and 2C isoforms of human fetal adrenal in T metabolism which respond to T metabolism in liver. Isolation and identification of T and its metabolites were carried out by isocratic high-performance liquid chromatography. CYP isoforms involved in T metabolism were examined by an inhibition study. Four metabolites formed by fetal adrenal microsomes were androstenedione (A), 16alpha-hydroxytestosterone (16alpha-HT), 16beta-hydroxytestosterone (16beta-HT) and 6beta-hydroxytestosterone (6beta-HT), which made up 61%, 25%, 12% and 2%, respectively, of the total. However, fetal liver microsomes produced six metabolites, which were, from high to low: A, 2alpha-HT, 6beta-HT, 2beta-HT, 16beta-HT and 16alpha-HT. Generation of A, 16alpha-HT and 16beta-HT in the adrenals was much greater than that in the liver. Erythromycin inhibited the formation of 6beta-HT and 16beta-HT with maximal inhibition of 76% and 47%. Sulfaphenazole and omeprazone had no inhibitive effect on the formations of T metabolites. The predominant metabolites of T in fetal adrenal, A and 16alpha-HT, were not decreased by these three inhibitors. These results suggest that the human fetal adrenal has greater T-metabolizing ability and a different metabolizing pathway from adult and fetal liver. Some other CYPs but not CYP3A7, CYP2C9 and CYP2C19 might play the most important part in the metabolism of T in human fetal adrenal although CYP3A7 is responsible for the formation of 6beta-HT and partly participates in the formation of 16beta-HT.
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China. clbwhcbd@yahoo.com
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: R X
authors.initials: RX
authors.lastname: Peng
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
mesh_terms: D000311:Adrenal Glands / Q000196:embryology* / Q000378:metabolism*; D000328:Adult; D000367:Age Factors; D000735:Androstenedione / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005865:Gestational Age; D006801:Humans; D006915:Hydroxytestosterones / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006915:Hydroxytestosterones; D007527:Isoenzymes; C400322:cytochrome P-450 CYP2C subfamily; D013739:Testosterone; D000735:Androstenedione; C025591:6 beta-hydroxytestosterone; C045261:16-hydroxytestosterone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A