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J.Health Sci., 49(4), 298-310, 2003
Metabolic Activation of Proestrogenic Diphenyl and Related Compounds by Rat Liver
Microsomes
Shigeyuki Kitamura,*, a Seigo
Sanoh,a Ryuki
Kohta,a Tomoharu
Suzuki,a Kazumi
Sugihara,a Nariaki
Fujimoto,b and Shigeru
Ohtaa
aGraduate School of Biomedical Sciences and
bResearch Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi
1-2-3, Minami-ku, Hiroshima 734-8551, Japan
In this study, liver microsome-mediated activation of diphenyl (DP), diphenylmethane (DPM) and
2,2-diphenylpropane (DPP) to estrogens was demonstrated. These three compounds were negative in estrogen
reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, they exhibited
estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the cases of DP and
DPM, or of phenobarbital-treated rats in the cases of DP and DPP, in the presence of NADPH. When these
compounds were incubated with liver microsomes in the presence of NADPH, monohydroxyl and dihydroxyl
derivatives were formed. These hydroxylated metabolites, 4-hydroxydiphenyl, 3-hydroxydiphenyl,
2-hydroxydiphenyl, 4-hydroxydiphenylmethane, 2-(4-hydroxyphenyl)-2-phenylpropane (4-OH-DPP),
4,4'-dihydroxydiphenyl, 4,4'-dihydroxydiphenylmethane and 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), all
exhibited estrogenic activity in MCF-7 cells. Binding assay of these hydroxylated compounds with rat uterus
estrogen receptor was also positive. These results suggest that the estrogenic activities of DP, DPM and DPP
were due to the formation of hydroxylated metabolites by the liver cytochrome P450 system.
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