Induction of hepatic cytochrome P4501A1/2B activity and disruption of thyroglobulin synthesis/secretion by mono-ortho polychlorinated biphenyl and its hydroxylated metabolites in rat cell lines.
As the active metabolites of polychlorinated biphenyl (PCBs), hydroxylated polychlorinated biphenyls (OH-PCBs) are found in wildlife and human tissues. They have been proposed as main contributors for endocrine disruption of PCBs in living organisms. In this study, mono-ortho PCB 156 and its hydroxylated metabolites 4'-OH-PCB 159, 4'-OH-PCB 121, and 4'-OH-PCB 72 were selected to investigate the toxic effects on rat hepatoma H4IIE cell line and rat thyroid follicle FRTL-5 cell line at concentrations of 1, 10(2), 10(4) nM. 7-Ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) activities were determined with micro-EROD/PROD to indicate cytochrome P4501A1 (CYP1A1) and cytochrome P4502B (CYP2B) induction in the H4IIE cell after exposure for 72 h. To assess thyroid disruption of these compounds, thyroglobulin concentrations also were detected inside FRTL-5 cell with immunocellularchemistry and in its medium with radioimmunoassay after exposure for 24 h. Significant inductions of EROD activity by PCB156 at 10(2) and 10(4) nM (p < 0.05) were observed, but no effects by the three OH-PCBs in H4IIE cell line. 7-Pentoxyresorufin-O-dealkylase activities were induced only by 10(4) nM of PCB156 and the three OH-PCBs (p < 0.05). Meanwhile, significant increases of thyroglobulin concentrations were observed in the medium of FRTL-5 cell exposed to 4'-OH-PCB 121 and 4'-OH-PCB 72 at all of the test concentrations (p < 0.05), but not to the other compounds. The results demonstrated that mono-ortho PCBs mainly could be metabolized to hydroxylated metabolites through CYP1A1 instead of CYP2B. Moreover, after being metabolized, OH-PCBs still sustained the ability to induce PROD activity and did exhibit the disruption on thyroglobulin synthesis/excretion in rat cells.
Yang
Fangxing
F
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, People's Republic of China.
Xu
Ying
Y
Pan
Hongmei
H
Wu
Desheng
D
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000494:pharmacology; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology; D008660:Metabolism; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013954:Thyroglobulin / Q000096:biosynthesis* / Q000378:metabolism
D052244:Endocrine Disruptors; D013954:Thyroglobulin; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1