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Shigeyuki Kitamura,¹ Tomoharu Suzuki,¹ Shigeru Ohta,¹ and Nariaki Fujimoto²

¹Graduate School of Biomedical Sciences, and ²Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Abstract

We investigated the endocrine-disrupting actions of the organophosphorus pesticide fenthion and related compounds and the influence of metabolic transformation on the activities of these compounds. Fenthion acted as an antagonist of the androgenic activity of dihydrotestosterone (10^-7 M) in the concentration range of 10^-6-10^-4 M in an androgen-responsive element-luciferase reporter-responsive assay using NIH3T3 cells. The antiandrogenic activity of fenthion was similar in magnitude to that of flutamide. Fenthion also tested positive in the Hershberger assay using castrated male rats. Marked estrogenic and antiestrogenic activities of fenthion and related compounds were not observed in MCF-7 cells. When fenthion was incubated with rat liver microsomes in the presence of NADPH, the antiandrogenic activity markedly decreased, and fenthion sulfoxide was detected as a major metabolite. The oxidase activity toward fenthion was exhibited by cytochrome P450 and flavin-containing monooxygenase. Fenthion sulfoxide was negative in the screening test for antiandrogens, as was fenthion sulfone. However, when fenthion sulfoxide was incubated with liver cytosol in the presence of 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, the extract of the incubation mixture exhibited antiandrogenic activity. In this case, fenthion was detected as a major metabolite of the sulfoxide. Metabolic interconversion between fenthion and fenthion sulfoxide in the body seems to maintain the antiandrogenic activity. Key words: aldehyde oxidase, antiandrogenic activity, cytochrome P450, endocrine disruption, fenthion, fenthion sulfoxide. Environ Health Perspect 111:503-508 (2003) .