Effect of PCB153 on BaP-induced genotoxicity in HepG2 cells via modulation of metabolic enzymes.
Benzo(a)pyrene (BaP) is a representative environmental carcinogen and is metabolically activated by several cytochrome P450 (CYP) enzymes to become the ultimate carcinogen. Numerous studies have indicated that 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) could effectively alter the activity of xenobiotic metabolizing enzymes (XMEs). Therefore, we propose that PCB153 may affect BaP-induced genotoxicity mediated by XMEs. In the present study, we treated HepG2 cells with BaP (50 microM) or PCB153 (0.1, 1, 10 and 100 microM), or pretreated the cells with PCB153 for 48 h followed by treatment with a combination of both BaP and PCB153. CYP1A1 activity was dramatically increased in cells treated with either BaP or PCB153. Glutathione-S-transferase (GST) activity was increased in BaP-treated cells, but decreased in PCB153-treated cells. In parallel to studies on enzyme activity, the micronuclei (MN) assay was used to assess the genotoxic damage caused by BaP and PCB153. BaP and PCB153 at 100 microM enhanced MN formation. In contrast to BaP treatment alone, treatment with both BaP and PCB153 significantly enhanced the activity of CYP1A1 and the formation of MN, but reduced the activity of GST. alpha-Naphthoflavone (ANF), an inhibitor of CYP1A1, inhibited MN formation in the presence of both BaP and PCB153. In addition, there was a positive correlation between CYP1A activity and MN formation (r(2)=0.794, P<0.001). Our observations suggest that co-exposure to BaP and PCB153 may increase BaP-induced genotoxicity, possibly through the induction of CYP1A1 and inhibition of GST.
Wei
Wei
W
Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Zhang
Chi
C
Liu
Ai-Lin
AL
Xie
Shao-Hua
SH
Chen
Xue-Min
XM
Lu
Wen-Qing
WQ
D001564:Benzo(a)pyrene / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*
D001571:Benzoflavones; D001564:Benzo(a)pyrene; C011512:alpha-naphthoflavone; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; C014024:2,4,5,2',4',5'-hexachlorobiphenyl