Antiandrogenic activity and metabolism of the organophosphorus pesticide fenthion and related compounds.

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.

Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities

“…In contrast, reverse reductive metabolism of methiocarb sulfoxide to methiocarb may be mediated by aldehyde oxidase. A similar observation has been made in the reduction of fenthion sulfoxide (Kitamura et al, 2003). The carbamoyl moiety in carbamate pesticides contains either an ester bond or an amide bond.…”

“…In fact, we have reported that the anti-androgenic activity of fenthion, an organophosphate pesticide, is lost upon oxidation to fenthion sulfoxide by rat liver microsomes. However, the fenthion is recovered by the reduction of the sulfoxide (Kitamura et al, 2003). In contrast, the metabolites from the hydrolysis of methiocarb and carbaryl showed activities similar to or higher than those of the parent compounds.…”

“…Some chemicals such as methoxychlor, trans-stilbene, benzo[a]pyrene, 2-nitrofluorene, and styrene oligomers are negative in in vitro estrogen screening tests but exhibit estrogenic activity after they are metabolized by the microsomal CYP system (Kitamura et al, 2008). The anti-androgenic activity of fenthion, which is an organophosphate pesticide, was markedly decreased after its oxidative metabolism by liver microsomes (Kitamura et al, 2003). Thus, it is important to consider the effects of metabolic modification of pesticides.…”

Risk Assessment of Fenthion Oxide Derivatives in Aqueous Environment

“…Two major metabolites, MPP sulfoxide and MPP oxon were formed from MPP by some CYP and flavin-containig monooxygenase in the previously reported papers (Leoni et al, 2008;Kitamura et al, 2003). In their results, MPP sulfone and MPP oxon sulfone were not detected on chromatograms by HPLC/UV and GC/MS.…”

Sex-, tissue-, and exposure duration-dependent effects of imidacloprid modulated by piperonyl butoxide and menadione in rats. Part I: oxidative and neurotoxic potentials

“…It also lowered IMI-induced tGSH, while GPx decreased and CAT increased. Kitamura et al (68) reported that AOX catalysed fenthion metabolism to fenthion sulphoxide, and that this transformation was inhibited by MEN and β-oestradiol in the liver of male Sprague-Dawley rats. Similarly, Honda et al (8) reported that MEN decreased AOX activity in mouse fibroblast M10 cells.…”