title: Effect of metals on polycyclic aromatic hydrocarbon induction of CYP1A1 and CYP1A2 in human hepatocyte cultures.
abstract: Environmental cocontamination by polycyclic aromatic hydrocarbons (PAHs) and metals could affect the carcinogenic consequences of PAH exposure by modifying PAH induction of PAH-bioactivating CYP1A. The effect of As, Pb, Hg, or Cd (ranked as the most hazardous environmental metals by EPA and ATSDR) on CYP1A1 and 1A2 induction by benzo[a]pyrene (BaP), benzo[b]fluoranthene (BbF), dibenzo[a,h]anthracene (DBahA), benzo[a]anthracene (BaA), and benzo[k]fluoranthene (BkF) has thus been investigated in fresh human hepatocyte cultures. Induction was probed by ethoxyresorufin-O-deethylase activity, by immunoblots, and by RT-PCR. Uptake of PAHs into the hepatocytes varied according to PAH and liver donor: 84% of 5 microM BaA and 25-40% of 5 microM DBahA was taken up in 24 h. Hepatocytes retained viability up to 1 microM Cd and 5 microM Pb, Hg, or As and 5 microM PAHs. PAH induction of CYP1A in hepatocytes was variable, some cultures expressed CYP1A1 and others CYP1A1 and 1A2, and to variable extents. Induction efficiency (relative to DMSO controls) at 2.5 microM PAH concentration was in the order BkF (7.6-fold) > DBahA (6.1 fold) > BaP (5.7 fold) > BbF (3.9-fold) > BaA (2.5-fold). All four metals (1-5 microM) decreased CYP1A1/1A2 induction by some of the PAHs with dose-, metal-, and PAH-dependency. Arsenic (5 microM) decreased induction by 47% for BaP, 68% for BaA, 45% for BbF, 79% for BkF, and 53% for DBahA. Induced CYP1A2 protein was much more extensively decreased than 1A1 protein, and CYP1A2 mRNA and, to variable extents, CYP1A1 mRNA were decreased by As. Thus the metals in PAH/metal mixtures could diminish PAH carcinogenicity by decreasing induction of their bioactivation by CYP1A1/1A2.
authors.affiliation: New York State Department of Health, Wadsworth Center, Albany, New York 12201-0509, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Vakharia
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Pause
authors.forename: M
authors.initials: M
authors.lastname: Fasco
authors.forename: E
authors.initials: E
authors.lastname: Bessette
authors.forename: Q Y
authors.initials: QY
authors.lastname: Zhang
authors.forename: L S
authors.initials: LS
authors.lastname: Kaminsky
mesh_terms: D001151:Arsenic / Q000633:toxicity; D018053:Arsenites / Q000633:toxicity; D001711:Biotransformation / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics / Q000633:toxicity*; D002413:Cations, Divalent; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D019216:Metals, Heavy / Q000633:toxicity*; D011084:Polycyclic Aromatic Hydrocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; D002413:Cations, Divalent; D019216:Metals, Heavy; D011084:Polycyclic Aromatic Hydrocarbons; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C015001:arsenite; D001151:Arsenic