CYTOTOXICITY AND GENOTOXICITY OF (+ -)-BENZO[A]PYRENE-TRANS-7,8-DIHYDRODIOL IN CYP1A1-EXPRESSING HUMAN FIBROBLASTS QUANTITATIVELY CORRELATEWITH CYP1A1 EXPRESSION LEVEL/

Cytochrome P450 1A1 (CYP1A1) activity is associated with increased sus ceptibility 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 p roximate BP mutagenic metabolite, (-)-benzo[a]pyrene-trans-7,8-dihydro diol, to benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide, the ultima te BP mutagen. We have genetically engineered both DNA repair-deficien t (xeroderma pigmentosum group A) and DNA repair-proficient human skin fibroblasts to express human CYP1A1 under control of the inducible mo use metallothionein-I promoter. CYP1A1 activity was induced by CdSO4 a nd monitored by following the O-deethylation of ethoxy fluorescein eth yl ester or of 7-ethoxyresorudin. Induced CYP1A1 activities were simil ar in both cell lines and were dependent on CdSO4 concentration and in duction time. Maximal CYP1A1 activities were obtained in 46 h with 5-7 mu M 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 cell s than in DNA repair-proficient cells. The results suggest that modest ly induced CYP1A1 activity is a risk factor in polycyclic aromatic hyd rocarbon-induced carcinogenesis.