Abstract
Effects of methoxychlor and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on 3ß-hydroxysteroid dehydrogenase and 17ß-hydroxysteroid dehydrogenase-3 activities in human and rat testes
Hu,Guo-Xin; Zhao,Binghai; Chu,Yanhui; Li,X.H.; Akingbemi,Benson T.; Zheng,Zhi-Qiang; Ge,Renshan
International Journal of Andrology 34(2): 138-144
Publication date: 2011
Human and rat testis microsomes were used to investigate direct inhibitory activities of methoxychlor (MXC) and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3). The 3ß-HSD and 17ß-HSD3 enzymes are involved in the reactions that culminate in androgen biosynthesis in Leydig cells. The results demonstrated that MXC and HPTE inhibited human 3ß-HSD activity at a concentration of 10 nm. The half maximal inhibitory concentration (IC) for MXC inhibition of 3ß-HSD was 53.21 ± 15.52 µm (human) and 46.15 ± 17.94 µm (rat), and for HPTE, it was 8.29 ± 2.49 µm (human) and 13.82 ± 2.26 µm (rat). At the higher concentration of 100 µm, MXC did not affect human and rat 17ß-HSD3 activity. However, the IC for HPTE inhibition of 17ß-HSD3 was 12.1 ± 1.9 µm (human) and 32 .0 ± 8.6 µm (rat). The mode of action of MXC and HPTE on 3ß-HSD activity was non-competitive with the substrate pregnenolone, but was competitive with the cofactor NAD. The mode of HPTE inhibition of 17ß-HSD3 was non-competitive with the substrate androstenedione, but was competitive with the cofactor NADPH. In summary, our results showed that HPTE, which is the biologically active metabolite of MXC, has the capacity for direct inhibition of 3ß-HSD and 17ß-HSD3 enzyme activity. Inhibition of enzyme activity is presumably associated with suppression of steroidogenesis in gonadal tissues and has implications for testis function.
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