title: Dithioerythritol (DTE) prevents inhibitory effects of triphenyltin (TPT) on the key enzymes of the human sex steroid hormone metabolism.
abstract: Organotins are known to induce imposex (pseudohermaphroditism) in marine neogastropods and are suggested to act as specific endocrine disruptors, inhibiting the enzyme-mediated conversion of steroid hormones. Therefore, we investigated the in vitro effects of triphenyltin (TPT) on human 5alpha-reductase type 2 (5alpha-Re 2), cytochrome P450 aromatase (P450arom), 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD 3), 3beta-HSD type 2 and 17beta-HSD type 1 activity. First, the present study demonstrates that significant amounts of TPT occurred in the blood of eight human volunteers (0.17-0.67 microg organotin cation/l, i.e. 0.49-1.92 nmolcation/l). Second, TPT showed variable inhibitory effects on all the enzymes investigated. The mean IC(50) values were 0.95 microM for 5alpha-Re 2 (mean of n=4 experiments), 1.5 microM for P450arom (n=5), 4.0 microM for 3beta-HSD 2 (n=1), 4.2 microM for 17beta-HSD 3 (n=3) and 10.5 microM for 17beta-HSD 1 (n=3). To exclude the possibility that the impacts of TPT are mediated by oxidizing essential thiol residues of the enzymes, the putative compensatory effects of the reducing agent dithioerythritol (DTE) were investigated. Co-incubation with DTE (n=3) resulted in dose-response prevention of the inhibitory effects of 100 microM deleterious TPT concentrations on 17beta-HSD 3 (EC(50) value of 12.9 mM; mean of n=3 experiments), 3beta-HSD 2 (0.90 mM; n=3), P450 arom (0.91 mM; n=3) and 17beta-HSD 1 (0.21 mM; n=3) activity. With these enzymes, the use of 10mM DTE resulted in an at least 80% antagonistic effect, whereas, the effect of TPT on 5alpha-Re 2 was not compensated. In conclusion, the present study shows that TPT acts as an unspecific, but significant inhibitor of human sex steroid hormone metabolism and suggests that the inhibitory effects are mediated by the interaction of TPT with critical cysteine residues of the enzymes.
authors.affiliation: Department of Clinical Biochemistry, Institut für Klinische Biochemie, Universität Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Lo
authors.forename: Axel
authors.initials: A
authors.lastname: Alléra
authors.forename: Peter
authors.initials: P
authors.lastname: Albers
authors.forename: Jörg
authors.initials: J
authors.lastname: Heimbrecht
authors.forename: Eckard
authors.initials: E
authors.lastname: Jantzen
authors.forename: Dietrich
authors.initials: D
authors.lastname: Klingmüller
authors.forename: Stephan
authors.initials: S
authors.lastname: Steckelbroeck
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000293:Adolescent; D000328:Adult; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors; D004226:Dithioerythritol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D009947:Organotin Compounds / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology; D013737:Testis / Q000201:enzymology
chemical_list: D058891:5-alpha Reductase Inhibitors; D047072:Aromatase Inhibitors; D012739:Gonadal Steroid Hormones; D009947:Organotin Compounds; D004226:Dithioerythritol; C030665:triphenyltin; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase