Potency of various polycyclic aromatic hydrocarbons as inducers of CYP1A1 in rat hepatocyte cultures

A number of highly toxic environmental pollutants including certain polychl orinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), an d 'dioxin-like' polychlorinated biphenyls (PCB) are among the most potent a gonists of the aryl hydrocarbon receptor (AHR). Induction of cytochrome P45 01A1 (CYP1A1) in mammalian cell culture is widely used as a functional para meter for AHR activation providing an estimate for 'dioxin-like' inducing e quivalents in extracts from environmental samples. Since a number of polycy clic aromatic hydrocarbons (PAHs) also act as AHR-agonists, the CYP1A1-indu cing potencies, measured as induction of 7-ethoxyresorufin O-deethylase (ER OD) activity in rat hepatocyte cultures were analyzed for 16 PAHs frequentl y present in environmental samples. Among these, seven PAHs including benzo [a]pyrene were relatively potent inducers allowing the determination of Ind uction Equivalency Factors (IEF). For three PAHs including benzo[k]fluorant hene which acted as weak inducers, IEFs were estimated, while six PAHs incl uding acenaphthylene were classified as inactive. Based on different effica cies the concentration-response characteristics of CYP1A1 induction were an alyzed in mon detail for benzo[a]pyrene, benzo[k]fluoranthene, and acenapht hylene. Benzo[k]fluoranthene was markedly less effective than benzo[a]pyren e as inducer of EROD activity but even more effective than benzo[a]pyrene a s inducer of CYP1A1 protein and mRNA. Acenaphthylene was highly more effect ive on the level of mRNA than on the levers of protein or EROD activity. Fu rther analysis revealed that the low efficacy of acenaphthylene as inducer of CYP1A1 protein and EROD activity is due to its marked cytotoxicity while no clear-cut explanation was found for the differences in efficacy between benzo[k]fluoranthene and benzo[a]pyrene. The EROD-inducing potency of a mi xture of 16 PAH was about 2-fold higher than that calculated on the basis o f IEFs of the individual constituents of the mixture. (C) 1999 Elsevier Sci ence Ireland Ltd. All rights reserved.