Abstract
CYP1A1 and 1A2 play critical roles in the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines/amides (HAAs), respectively, to electrophilic reactive intermediates, leading to toxicity and cancer. CYP1As are highly inducible by PAHs and halogenated aromatic hydrocarbons via aryl hydrocarbon receptor-mediated gene transcription. The impact of CYP1A induction on the carcinogenic and toxic potentials of environmental, occupational, dietary, and therapeutic chemicals has been a central focus of human risk evaluation and has broadly influenced the fields of cancer research, toxicology, pharmacology, and risk assessment over the past half-century. From the early discovery of CYP1A induction and its role in protection against chemical carcinogenesis in intact animals, to the establishment of CYP1A enzymes as the principal cytochromes P450 for bioactivation of PAHs and HAAs in in vitro assays, to the recent realization of an essential protective role of CYP1A in benzo[a]pyrene-induced lethality and carcinogenesis with CYP1A knockout mice, the understanding of the interrelation between CYP1A induction and chemical safety has followed a full circle. This unique path of CYP1A research underscores the importance of whole animal and human studies in chemical safety evaluation.
Footnotes
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Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.015826.
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ABBREVIATIONS: PAH, polycyclic aromatic hydrocarbon; P450, cytochrome P450; HAA, heterocyclic aromatic amine/amide; B[a]p, benzo[a]pyrene; 3-MC, 3-methylcholanthrene; 3′-Me-DAB, 3′-methyl-4-dimethylaminoazobenzene; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; AHH, aryl hydrocarbon hydroxylase; Ah, aromatic hydrocarbon responsiveness locus; AhR, aryl hydrocarbon receptor; Arnt, Ah receptor nuclear translocator; B6, C57BL/6; D2, DBA/2; ABP, 4-aminobiphenyl; DDI, drug-drug interaction; bHLH, basic helix-loop-helix; PAS, Per-Arnt-Sim homology domain; EM, extensive metabolizer; PM, poor metabolizer.
- Received March 16, 2007.
- Accepted April 11, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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