Testosterone-metabolizing capacity and characteristics of adrenal microsomes in human fetus in vitro.
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.
Wang
Hui
H
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China. clbwhcbd@yahoo.com
Xu
Dan
D
Peng
R X
RX
Yue
Jiang
J
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*
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