Inducing effects of dioxin-like polychlorinated biphenyls on CYP1A in the human hepatoblastoma cell line HepG2, the rat hepatoma cell line H4IIE, and rat primary hepatocytes: comparison of relative potencies.
Polychlorinated biphenyls (PCBs) are a group of widespread environmental pollutants. Some non-ortho-substituted congeners with a high likelihood of coplanarity of both aromatic rings have been shown to act like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as agonists of the aryl hydrocarbon receptor (AhR) subsequently leading to adverse effects, such as immunosuppression and tumor promotion. Although there is a broad base of experimental data concerning the toxicity of PCBs in laboratory animals and animal-derived primary cells and cell lines, only few experimental data are available for cells of human origin. As a parameter of AhR activation, induction of CYP1A-mediated 7-ethoxyresorufin O-deethylase (EROD) activity was determined in the human hepatoblastoma cell line HepG2 treated with the PCBs IUPAC Nos. 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189, and with TCDD as a positive control. Compared with results in rat primary hepatocytes and the rat hepatoma cell line H4IIE, treated HepG2 cells showed lower specific EROD activities maximally inducible by TCDD and PCBs, and EC50 values were shifted to higher concentrations. Furthermore, relative potency factors (REPs) for some congeners such as PCBs 81, 126, and 169 greatly differed from those observed in cells derived from rats. Northern blot analyses showed that EROD activities run parallel to changes in CYP1A-specific mRNA contents. The considerable differences in EROD-derived REPs between cells of human and rat origin indicate the need for further investigations in experimental models from different species including humans in order to extend the database of biochemical and toxic responses to PCBs.
Zeiger
M
M
Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Erwin-Schroedinger-Str. 52, D-67663 Kaiserslautern, Germany.
Haag
R
R
Höckel
J
J
Schrenk
D
D
Schmitz
H J
HJ
D000818:Animals; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D018197:Hepatoblastoma; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1