Inhibition of human cytochrome P450 aromatase activity by butyltins.
Organotin compounds are widely used as antifouling agents and bioaccumulate in the food chain. Tributyltin chloride (TBT) has been shown to induce imposex in female gastropods. On the basis of this observation it has been suggested that TBT acts as an endocrine disrupter inhibiting the conversion of androgens to estrogens mediated by the aromatase cytochrome P450 enzyme. However, to date, the molecular basis of TBT-induced imposex and in particular its putative inhibitory effects on human aromatase cytochrome P450 activity have not been investigated. Therefore, we examined the effects of the organotin compounds tetrabutyltin (TTBT), TBT, dibutyltin dichloride (DBT) and monobutyltin trichloride (MBT) on human placental aromatase activity. TBT was found to be a partial competitive inhibitor of aromatase activity with an IC(50) value of 6.2 microM with 0.1 microM androstenedione as substrate. TBT impaired the affinity of the aromatase to androstenedione but did not affect electron transfer from NADPH to aromatase via inhibiting the NADPH reductase. DBT acted as a partial but less potent inhibitor of human aromatase activity (65% residual activity), whereas TTBT and MBT had no effect. The residual activity of TBT-saturated aromatase was 37%. In contrast, human 3beta-HSD type I activity was only moderately inhibited by TBT (80% residual activity). Moreover, neither TTBT or DBT nor MBT inhibited the 3beta-HSD type I activity. Together, these results suggest that the environmental pollutants TBT and DBT, both present in marine organisms, textile and plastic products, may have specific impacts on the metabolism of sex hormones in humans.
Heidrich
D D
DD
Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Strasse 25, D-53125, Bonn, Germany. d.heidrich@gmx.de
Steckelbroeck
S
S
Klingmuller
D
D
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000494:pharmacology; D009947:Organotin Compounds / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D009947:Organotin Compounds; D000735:Androstenedione; D009249:NADP; D015096:3-Hydroxysteroid Dehydrogenases; D001141:Aromatase