Metabolic Activation of Proestrogenic Diphenyl and Related Compounds by Rat Liver Microsomes

Shigeyuki Kitamura, Seigo Sanoh, Ryuki Kohta, Tomoharu Suzuki, Kazumi Sugihara, Nariaki Fujimoto, Shigeru Ohta
2003 Journal of health science  
In this study, liver microsome-mediated activation of diphenyl (DP), diphenylmethane (DPM) and 2,2diphenylpropane (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
more » ... 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. Key words ---diphenyl, estrogenic activity, metabolic activation, human breast cancer cell line MCF-7, endocrine disruption, cytochrome P450 exert biological effects. Many so-called xenoestrogens produce a wide variety of toxic effects in animals. They may be playing a role in the increasing incidence of hormonally related cancers such as breast cancer and testicular cancer, and other problems of the reproductive system in humans. It is therefore important to screen environmental contaminants for estrogenic activity. Their metabolites also need to be identified and screened. We recently showed that trans-stilbene, which is the parent compound of diethylstilbestrol, and trans-stilbene oxide were not estrogenic, but exhibited a potent estrogenic activity after metabolic activation by a liver microsomal oxidation system. 4, 5) In that report, we suggested that the estrogenic activity was due to the hydroxylated metabolites, trans-4-hydroxystilbene and trans-4,4′-dihydroxystilbene, formed by cytochrome P450 1A1/2. Furthermore, we demonstrated that styrene oligomers were metabolically activated to estrogens by rat liver microsomes, especially cytochrome P450 2B1. 6) These results demonstrate the importance of considering proestrogenic potential, when screening for xenoestrogens in the environment. Fig. 6. Metabolic Pathways for the Activation of DP, DPM and DPP by Rat Liver Microsomes CYP, cytochrome P450.
doi:10.1248/jhs.49.298 fatcat:zjbmtvcuz5dcnaam6gauigbhiy