title: Detection and measurement of the agonistic activities of PCBs and mono-hydroxylated PCBs to the constitutive androstane receptor using a recombinant yeast assay.
abstract: Polychlorinated biphenyls (PCBs) are thought to exert their toxicities mainly by binding to the aryl hydrocarbon receptor and by stimulating transcription of various genes, notably metabolizing enzymes including the cytochrome P450 (CYP) 1 family. However, PCBs and their metabolites could have potential to activate other nuclear receptors and subsequent events. We focused on the constitutive androstane receptor (CAR) inducing CYP2B and measured the agonistic activity of PCBs and mono-hydroxylated PCBs (OH-PCBs) to the CAR using yeast cells transduced with the human CAR and its response pathway. Twenty-nine of 34 tested PCBs and 72 of 91 OH-PCBs exhibited CAR agonistic effects. Of 41 OH-PCBs that had the same chlorination patterns as the tested PCBs, 9 had activities more than twice those of their non-hydroxylated analogs. In particular, 2',4',6'-trichlorobiphenyl-4-ol and 2,2',4',6'-tetrachlorobiphenyl-4-ol were 332- and 22-fold more potent than their analogs and were 15 times and 2.8 times, respectively, as active as a reference substance, 4-tert-octylphenol. The activities of 17 of the OH-PCBs were reduced to less than half those of their non-hydroxylated analogs. Four OH-PCBs derived from 3 active PCBs were inactive. However, a consistent relationship between hydroxyl substituent position and activity could not be discerned. Comprehensive evaluation of the toxic potential of PCBs and their hydroxylated metabolites and their concentrations in the environment are required.
authors.affiliation: Laboratory of Toxicology, School of Veterinary Medicine, Kitasato University, 35-1 Higashi 23-Bancho, Towada-shi, Aomori 034-8628, Japan. Electronic address: kamata@vmas.kitasato-u.ac.jp.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kamata
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Fujio
authors.initials: F
authors.lastname: Shiraishi
authors.affiliation: Faculty of Home Economics, Koriyama Women's University, 3-25-2 Kaisei, Koriyama, Fukushima 963-8503, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Kageyama
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakajima
mesh_terms: D001681:Biological Assay; D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants / Q000633:toxicity*; D017930:Genes, Reporter; D006900:Hydroxylation; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants; D018160:Receptors, Cytoplasmic and Nuclear; D011078:Polychlorinated Biphenyls; D001616:beta-Galactosidase
keywords: 2,2′,4′,6′-Tetrachlorobiphenyl-4-ol (4′-OH-CB50); 2′,4′,6′-Trichlorobiphenyl-4-ol (4′-OH-CB30); Constitutive androstane receptor; Hydroxylated PCB; Polychlorinated biphenyls; Recombinant yeast