Cytotoxicity and genotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol in CYP1A1-expressing human fibroblasts quantitatively correlate with CYP1A1 expression level.
Cytochrome P450 1A1 (CYP1A1) activity is associated with increased susceptibility to lung cancer induced by polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BP). In non-hepatic human tissues, CYP1A1 is the principal enzyme responsible for the metabolic activation of the proximate BP mutagenic metabolite, (-)-benzo[a]pyrene-trans-7,8-dihydrodiol, to (+)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide, the ultimate BP mutagen. We have genetically engineered both DNA repair-deficient (xeroderma pigmentosum group A) and DNA repair-proficient human skin fibroblasts to express human CYP1A1 under control of the inducible mouse metallothionein-I promoter. CYP1A1 activity was induced by CdSO4 and monitored by following the O-deethylation of ethoxy fluorescein ethyl ester or of 7-ethoxyresorufin. Induced CYP1A1 activities were similar in both cell lines and were dependent on CdSO4 concentration and induction time. Maximal CYP1A1 activities were obtained in 4-6 h with 5-7 microM CdSO4. BPD-induced cytotoxicity and hypoxanthine phosphoribosyl transferase mutagenicity were both quantitatively correlated with the level of CYP1A1 activity and were greater in DNA repair-deficient cells than in DNA repair-proficient cells. The results suggest that modestly induced CYP1A1 activity is a risk factor in polycyclic aromatic hydrocarbon-induced carcinogenesis.
Quan
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Center for Molecular Biology, Wayne State University, Detroit, MI 48201.
Reiners
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JJ
Bell
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Hong
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States
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D002104:Cadmium / Q000633:toxicity; D019187:Cadmium Compounds; D003043:Cocarcinogenesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D004260:DNA Repair; D004101:Dihydroxydihydrobenzopyrenes / Q000633:toxicity*; D004790:Enzyme Induction; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D009153:Mutagens / Q000633:toxicity; D011083:Polycyclic Compounds / Q000633:toxicity; D012307:Risk Factors; D013431:Sulfates
D019187:Cadmium Compounds; D004101:Dihydroxydihydrobenzopyrenes; D009153:Mutagens; D011083:Polycyclic Compounds; D013431:Sulfates; D002104:Cadmium; C017228:benzo(a)pyrene 7,8-dihydrodiol; D003577:Cytochrome P-450 Enzyme System; C037123:cadmium sulfate