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Inhibition of human cytochrome P450 1A1-, 1A2-, and 1B1-mediated activation of procarcinogens to genotoxic metabolites by polycyclic aromatic hydrocarbons.

Shimada T, Guengerich FP
Chem Res Toxicol. 2006 19 (2): 288-94

PMID: 16485905 · DOI:10.1021/tx050291v

Many chemicals in the environment can cause cancer, and polycyclic aromatic hydrocarbons (PAHs) are among the most ubiquitous. Cancer risk assessments require consideration of these in complex mixtures. PAHs require metabolic activation by cytochrome P450 (P450) enzymes, primarily 1A1, 1A2, and 1B1. We determined if individual PAHs and other procarcinogens affect the activities of human P450s 1A1, 1A2, and 1B1 by measuring 7-ethoxyresorufin O-deethylation (EROD) activity and metabolic activation of PAH dihydrodiols and 2-amino-3,5-dimethylimidazo[4,5-f]quinoline (MeIQ) to genotoxic metabolites in a Salmonella typhimurium NM2009 system. Of 23 PAHs examined, benz[a]anthracene (B[a]A), benzo[b]fluoranthene, and 5-methylchrysene were the most potent inhibitors of P450 1A2- and 1B1-catalyzed EROD activity, with IC50 values <10 nM. Other PAHs, e.g., dibenz[a,c]anthracene, dibenz[a,h]anthracene, dibenz[a,j]acridine, and 3-methylcholanthrene, rather selectively inhibited P450 1B1, with IC50 values <15 nM. Benzo[a]pyrene (B[a]P) and nine other PAHs also inhibited P450 1A2 as well as 1B1 with IC50 values <150 nM. Parent PAH compounds were generally more potent than 10 dihydrodiol metabolites of PAHs and 3- and 9-hydroxy B[a]P in inhibiting EROD activity. In addition, we found that three selected PAHs (5-methylchrysene, B[a]P, and B[a]A) inhibited metabolic activation of 5-methylchrysene-1,2-diol, (+/-)-B[a]P-7,8-diol, dibenzo[a,l]pyrene-11,12-diol, and MeIQ to genotoxic metabolites catalyzed by P450s 1A1, 1B1, and 1A2, respectively, in S. typhimurium NM2009. Thus, individual PAHs may affect their own and metabolism of other carcinogens catalyzed by P450 1A1, 1A2, and 1B1, and these phenomena cause alteration in their ability to transform cells when single or complex PAH mixtures are ingested by mammals, influencing risk assessment.

MeSH Terms (13)

Aryl Hydrocarbon Hydroxylases Carcinogens Cytochrome P-450 CYP1A1 Cytochrome P-450 CYP1A2 Cytochrome P-450 CYP1A2 Inhibitors Cytochrome P-450 CYP1B1 Enzyme Activation Enzyme Inhibitors Humans Molecular Structure Polycyclic Aromatic Hydrocarbons Salmonella typhimurium Structure-Activity Relationship

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