Unique induction of cytochrome P-450 isozymes in rat liver microsomes by treatment with 3,4,5,3',4'-pentachlorobiphenyl and its effect on testosterone metabolism.

Yoshihara S.

The author started a research on xenobiotic metabolism at Graduate School of Pharmaceutical Sciences, Kyushu University in 1965. In 1968, an epidemic of a "strange disease", called Yusho, occurred in western Japan. The epidemic was soon identified to be a food poisoning caused by the ingestion of commercial Kanemi rice bran oil which had been accidentally contaminated with large amounts of polychlorinated biphenyls (PCBs) and their related compounds such as polychlorinated dibenzofurans (PCDFs.) At first, in this review, our toxicological studies on Yusho during the early thirty years were briefly described. Next, the studies on aldehyde oxidase, a molybdenum hydroxylase, which is involved in the lactam formation reaction such as 1-phenyl-2-(2-oxopyrrolidine)pentane(oxoprolintane) from 1-phenyl-2-pyrrolidinopentane(prolintane) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) lactam from 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP⁺) were also presented. Finally, we investigated how the xenobiotic metabolism of endocrine disrupting chemicals such as bisphenol A (BPA) and some isoflavones affects their estrogenic activities. In this study, we demonstrated that BPA is converted to 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an active metabolite as estrogen, by rat liver S9. In the cases of isoflavones, although genistein was inactivated, biochanin A, 4'-methoxy analogue of genistein, was activated to genistein by O-demethylation with rat liver S9.

Ishii Y., Iwanaga M., Nishimura Y., Takeda S., Ikushiro S., Nagata K., Yamazoe Y., Mackenzie P.I., Yamada H.

Klasson Wehler E., Hovander L., Lund B.

The metabolism of 14C-labeled 2,2',4,5,5'-pentachlorobiphenyl was studied in mink (Mustela vison) and, for comparison in the mouse (C57Bl). Both species were dosed orally and kept in metabolism cages for 5 days. Distribution in tissues and excretion rate were determined radiometrically, and metabolites were analyzed by GC/MS. Within 5 days, the mink excreted 17% of the dose, and the mouse excreted 74%, mainly via the feces. For both species, the excreted radioactivity consisted primarily of metabolites, a large proportion of which were covalently bound to macromolecules and to lipids. A smaller proportion consisted of water-soluble metabolites. Phenolic and, in trace amounts, methylsulfonyl metabolites were also excreted. In the mink, a salivary gland in the neck region demonstrated the highest concentration of radiolabeled material of all tissues examined (3 times higher than in adipose tissue and liver on a lipid weight basis). The radioactive material in the salivary gland consisted of the parent compound and phenolic and methylsulfonyl metabolites. In the mouse, the highest concentration of 14C was found in the lund and consisted of 4-methylsulfonyl-2,2',4',5,5'-pentachlorobiphenyl. Hydroxylated and methylsulfonyl metabolites were retained to various degrees in tissues of both species. The mink, but not the mouse, also formed metabolites that were hydroxylated in the trichlorinated phenyl ring.

Koga N., Nishimura N., Kuroki H., Masuda Y., Yoshimura H.

Safe S.H.

Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogs are Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds have utilized a toxic equivalency factor (TEF) approach for the hazard and risk assessment of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) congeners in which the TCDD or toxic TEQ = sigma([PCDFi x TEFi]n)+sigma([PCDDi x TEFi]n) equivalent (TEQ) of a mixture is related to the TEFs and concentrations of the individual (i) congeners as indicated in the equation (note: n = the number of congeners). Based on the results of quantitative structure-activity studies, the following TEF values have been estimated by making use of the data available for the coplanar and monoortho coplanar PCBs: 3,3',4,4',5-pentaCB, 0.1; 3,3',4,4',5,5'-hexaCB, 0.05; 3,3',4,4'-tetraCB, 0.01; 2,3,3',4,4'-pentaCB, 0.001; 2,3',4,4',5-pentaCB, 0.0001; 2,3,3',4,4',5-hexaCB, 0.0003; 2,3,3',4,4',5'-hexaCB, 0.0003; 2',3,4,4',5-pentaCB, 0.00005; and 2,3,4,4',5-pentaCB, 0.0002. Application of the TEF approach for the risk assessment of PCBs must be used with considerable caution. Analysis of the results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs may be both species- and response-dependent because both additive and nonadditive (antagonistic) interactions have been observed with PCB mixtures. In the latter case, the TEF approach would significantly overestimate the toxicity of a PCB mixture. Analysis of the rodent carcinogenicity data for Aroclor 1260 using the TEF approach suggests that this response is primarily Ah-receptor-independent. Thus, risk assessment of PCB mixtures that uses cancer as the endpoint cannot solely utilize a TEF approach and requires more quantitative information on the individual congeners contributing to the tumor-promoter activity of PCB mixtures.

GOLDSTEIN J.A., SAFE S.