RT Journal Article SR Electronic T1 Polycyclic Aromatic Hydrocarbon/Metal Mixtures: Effect on PAH Induction of CYP1A1 in Human HepG2 Cells JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 999 OP 1006 VO 29 IS 7 A1 Dilip D. Vakharia A1 Ning Liu A1 Ronald Pause A1 Michael Fasco A1 Erin Bessette A1 Qing-Yu Zhang A1 Laurence S. Kaminsky YR 2001 UL http://dmd.aspetjournals.org/content/29/7/999.abstract AB Environmental polycyclic aromatic hydrocarbons (PAHs) and metals coexist, and such mixtures could affect the carcinogenicity of PAHs, possibly by modification of PAH induction of the PAH-bioactivating CYP1A. The effect on PAH-mediated CYP1A induction of arsenic, lead, mercury, or cadmium (ranked as the most hazardous environmental metals by the Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry) has thus been investigated. Induction of CYP1A1 by benzo[a]pyrene (BAP), benzo[b]fluoranthene (BBF), dibenzo[a,h]anthracene (DBAHA), benzo[a]anthracene (BAA), or benzo[k]fluoranthene (BKF) was probed by ethoxyresorufin-O-deethylase activity (EROD) in 96-well plates of human HepG2 cells, by immunoblot analysis, and by reverse transcription-polymerase chain reaction. Cells rapidly took up PAHs (BAP, BKF) from medium; by 24 h only 14% remained in the medium, and no detectable PAH bound to well walls. Induction efficiency (relative to dimethyl sulfoxide controls) was in the order BKF (16-fold) > DBAHA (14-fold) > BAA (4-fold) > BAP (3-fold) > BBF (1-fold), all at 5 μM PAH. The metals did not markedly affect cell viability at concentrations of arsenic, 5 μM; lead, 50 μM; mercury, 5 μM; and cadmium, 5 μM. At 5 μM PAH concentration, all of the metals decreased levels of PAH-induced CYP1A1 activities (direct inhibition of EROD activity was excluded) by variable extents and in a PAH-dependent manner. With BAP as inducer decreases in induction were arsenic, 57%; cadmium, 82%; mercury, 4%; and lead, 20%. The decreases were not a consequence of transcriptional down-regulation. One possible conclusion is that these metals could diminish PAH carcinogenic potential by decreasing PAH-mediated induction of their bioactivation by CYP1A1. The American Society for Pharmacology and Experimental Therapeutics