CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies.
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.
Ma
Qiang
Q
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505, USA. qam1@cdc.gov
Lu
Anthony Y H
AY
D000588:Amines / Q000633:toxicity; D000818:Animals; D000897:Anti-Ulcer Agents / Q000009:adverse effects; D001564:Benzo(a)pyrene / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000633:toxicity; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D009853:Omeprazole / Q000009:adverse effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods
D000588:Amines; D000897:Anti-Ulcer Agents; D002273:Carcinogens; D006571:Heterocyclic Compounds; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D009853:Omeprazole