Metabolic Activation of the Proestrogens trans-Stilbene and trans-Stilbene Oxide by Rat Liver Microsomes

Sugihara, Kazumi; Kawa, Shigeyuki; Sanoh, Seigo; Ohta, Shigeru; Fujimoto, Nariaki; Maruyama, Satoshi; Ito, Akihiro

doi:10.1006/taap.2000.8979

Cited by 45 publications

(40 citation statements)

References 31 publications

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“…Polychlorinated biphenyls are converted to hydroxylated metabolites in animals, and some hydroxylated polychlorinated biphenyls show estrogenic and/or antithyroid hormonal activity (Connor et al 1997;Garner et al 1999;Korach et al 1988). Further, methoxychlor, trans-stilbene, benzophenone, and benzo [a]pyrene are proestrogens that require metabolic activation by liver microsomal mixed-function oxidase in animals (Charles et al 2000;Fertuck et al 2001;Gaido et al 1999;Nakagawa and Suzuki 2002;Sugihara et al 2000). In contrast, the estrogen screening Weights of the reproductive organs of rats were expressed.…”

Section: Discussionmentioning

confidence: 99%

“…We assayed estrogenic activity according to the previously reported method using an ERE-luciferase reporter in MCF-7 cells (Sugihara et al 2000). Briefly, transient transfections in MCF-7 cells were performed using TransFast in 12-well plates at 1 × 10 5 cells/well with 1.9 µg p(ERE) 3 -SV40-luc and 0.1 µg pRL-CMV as an internal standard.…”

Section: Fenthion [Oo-dimethyl-o-(4-methylmercapto)-3-methylphenylthmentioning

confidence: 99%

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

Kawa

Suzuki

Ohta

et al. 2003

Environ Health Perspect

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Fenthion [Oo-dimethyl-o-(4-methylmercapto)-3-methylphenylthmentioning

confidence: 99%

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

Kawa

Suzuki

Ohta

et al. 2003

Environ Health Perspect

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“…However, when transstilbene was incubated with liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH, the extract of the incubation mixture exhibited an estrogenic effect in the concentration range of 10 −5 -10 −6 M. In contrast, cis-stilbene showed little estrogenic activity after incubation with liver microsomes. 9) When trans-stilbene was incubated with liver microsomal enzyme system of 3-methylcholanthrene-treated rats, trans-4-hydroxystilbene and trans-4,4 -dihydroxystilbene were both formed, though trans-4-hydroxystilbene was predominant. Human cytochrome P450 1A1 and 1A2 isoforms expressed in human lymphoblastoid cells catalyzed both oxidations.…”

Section: Activation Of Trans-stilbene and Related Compounds By The Cymentioning

confidence: 96%

“…Several reports indicate that proestrogens, which act as xenoestrogens after metabolic activation, exist in the environment. [9][10][11][12][13][14][15][16] The potential of these proestrogens, such as methoxychlor, for endocrine disruption needs to be assessed.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Activation of Proestrogens in the Environment by Cytochrome P450 System

Kawa

Sugihara

Sanoh

et al. 2008

JOURNAL OF HEALTH SCIENCE

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Liver microsome-mediated activation of proestrogens in the environment is reviewed here. Proestrogens such as methoxychlor, trans-stilbene, diphenyl, diphenylmethane, 2,2-diphenylpropane, benzo[a]pyrene, benzophenone, 2-nitrofluorene (NF), chalcone, trans-4-phenyl-3-buten-2-one and styrene oligomers are negative in in vitro estrogen screening tests. However, those proestrogens exhibit estrogenic activity after metabolic activation by the microsomal cytochrome P450 system. In these cases, hydroxylated derivatives of the compounds are formed as major metabolites, and these metabolites exhibit significant estrogenic activities. Thus, the estrogenic activities of proestrogenic compounds are a consequence of metabolism of the parent compounds. Various candidates for proestrogens among medicines and insecticides are also discussed.

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“…For example, trans-stilbene and methoxychlor showed agonistic ER activity through metabolism. [16][17][18][19][20] However, the results showed that the metabolite of CDNB did not affect the estrogenic action (Fig. 4).…”

Section: Fig 5 Effect Of Cdnb On Ahr Activitymentioning

confidence: 99%

1-Chloro-2,4-Dinitrobenzene Stimulates the Estrogenic Activity in MCF-7 Cells

Jung

Ishida

Osada

et al. 2004

JOURNAL OF HEALTH SCIENCE

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The estrogenic effect of chemicals, including 1-chloro-2,4-dinitrobenzene (CDNB), in the combination with 17β-estradiol (E 2 ) was screened by a reporter gene assay using breast cancer cells (MCF-7). It was found that CDNB stimulated E 2 -induced transcriptional activity of estrogen receptor (ER) and down-regulated both ER protein and mRNA. However, CDNB alone and CDNB metabolite(s) showed no estrogenic activity and no binding activity to ER, suggesting an indirect pathway other than ER. CDNB gave no transcriptional activity for an aryl hydrocarbon receptor (AhR), suggesting no possibility of a pathway through cross-talk between AhR and ER. On the other hand, CDNB enhanced the mitogen activated protein kinase (MAPK) pathway, suggesting estrogenic action via MAPK. These results indicated that CDNB possessed estrogen-like activity in the transcription and regulation of ER though a different pathway from E 2 .

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Metabolic Activation of the Proestrogens trans-Stilbene and trans-Stilbene Oxide by Rat Liver Microsomes

Cited by 45 publications

References 31 publications

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

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

Metabolic Activation of Proestrogens in the Environment by Cytochrome P450 System

1-Chloro-2,4-Dinitrobenzene Stimulates the Estrogenic Activity in MCF-7 Cells

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