INHIBITION OF CYP1A1-DEPENDENT ACTIVITY BY THE POLYNUCLEAR AROMATIC HYDROCARBON (PAH) FLUORANTHENE

Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE mt hepatoma cells has been used ext ensively as a bioassay for halogenated aromatic hydrocarbons and more recently for PAHs. Fluoranthene (FL) is a prevalent PAK contaminant in diverse environmental samples, and FL did not induce CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity significantly in H4IIE c ells. However, in cells cotreated with 2 x 10(-5) M FL plus the potent inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or benzo[k]fluora nthene (BkF) (2 x 10(-8) M), there was a significant decrease in EROD activities. Furthermore, treatment of TCDD-induced rat microsomes with FL caused an 80% decrease in EROD activity. Studies showed that FL di d not affect induction of CYP1A1 protein or mRNA levels in H4IIE cells , and analysis of enzyme inhibition data using microsomal CYP1A1 indic ated that FL noncompetitively inhibited CYP1A1-dependent activity. P-3 2-Postlabeling revealed no significant FL-DNA adduct formation in H4II E cells treated with FL. However, in cells cotreated with FL plus BkF or benzo[a]pyrene (BaP), certain PAH-DNA adducts were induced 2-fold. This study demonstrated that FL is an inhibitor of CYP1A1-dependent en zyme activity in rat hepatoma H4IIE cells and that the genotoxic poten cy of some carcinogenic PAHs may be modulated by FL in mixtures contai ning relatively high levels of this compound. (C) 1998 Elsevier Scienc e Inc.