The long-term goal of this project is to understand the role of cytochrome P450 1A1 (CYP1A1) in toxicity caused by environmental pollutants. Cyp1a1 has a broad tissue distribution, is expressed very early in gestation, and is transcriptionally regulated by the Ah receptor (AHR). The environmental contaminants benzo[a]pyrene (BaP) and dioxin are ligands for the AHR. Toxicity caused by these pollutants is known to be AHR-mediated, BaP requiring metabolic activation and dioxin negligibly metabolized. Evidence is accumulating that CYP1A1 also mediates the toxicity of dioxin. It is increasingly clear that, in the most basic of terms, environmental toxicity of chemicals occurs via two routes: [a] covalent binding of reactive intermediates to cellular macromolecules and/or [b] activation of signal transduction pathways that ultimately influence the fate of specific cell types. With our recent success in making the Cyp1a1 (-/-) knockout mouse line, we are now in the unique position to delineate tissue- and cell type-specific CYP1A1- versus AHR-dependent and - independent modes of toxicity elicited by metabolized (BaP) and nonmetabolized (dioxin) AHR ligands. The work of others has unequivocally shown that about 15% to more than 25% (depending on the tissue) of CYP1A1 is located in the inner mitochondrial membrane (mt1A1), the remaining in the endoplasmic reticulum, i.e. microsomes (mc1A1), and that clear differences in the inducibility profile and substrate specificity exist between mt1A1 and mc1A1. Events very early in the apoptosis cascade (cytochrome c release, BCL2 function) also occur in the inner mitochondrial membrane. Thus, CYP1A1-dependent toxicity may be largely ascribed to one subcellular location of the enzyme versus another. Our hypothesis is that Bap and dioxin-induced toxicity of various tissues is primarily he result of CYP1A1 function. For the next funding period we therefore will [1] assess in the Cyp1a1 (-/-) knockout mouse, compared with the Cyp1a1 (+/+) wild-type, differential toxicity induced by BaP versus dioxin in the [a] bone marrow, [b] liver, and [c]developing embryo; and [2] generate exclusively mitochondrial CYP1A1-containing (mt1A1) and exclusively microsomal CYP1A1 - containing (mc1A1) knock-in mouse lines to dissect the mechanism of liver toxicity further. These studies will greatly enhance our understanding of mtCYP1A1 versus mcCYP1A1- mediated toxicity caused by environmental pollutants and perhaps lead to the design of drugs to shield against such toxicity of CYP1A1 substrates and AHR ligands, in the diet and especially for cigarette smokers and occupationally-exposed workers.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Velazquez, Jose M
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University of Cincinnati
Public Health & Prev Medicine
Schools of Medicine
United States
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Nebert, Daniel W (2017) Aryl hydrocarbon receptor (AHR): ""pioneer member"" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of ""sensors"" of foreign and endogenous signals. Prog Lipid Res 67:38-57
Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua et al. (2014) Mice deficient in the gene for cytochrome P450 (CYP)1A1 are more susceptible than wild-type to hyperoxic lung injury: evidence for protective role of CYP1A1 against oxidative stress. Toxicol Sci 141:68-77
Uno, Shigeyuki; Sakurai, Kenichi; Nebert, Daniel W et al. (2014) Protective role of cytochrome P450 1A1 (CYP1A1) against benzo[a]pyrene-induced toxicity in mouse aorta. Toxicology 316:34-42
Nebert, Daniel W; Shi, Zhanquan; Gálvez-Peralta, Marina et al. (2013) Oral benzo[a]pyrene: understanding pharmacokinetics, detoxication, and consequences--Cyp1 knockout mouse lines as a paradigm. Mol Pharmacol 84:304-13
Gálvez-Peralta, Marina; Shi, Zhanquan; Chen, Jing et al. (2013) Oral benzo[a]pyrene in Cyp1a1/1b1(-/-) double-knockout mice: Microarray analysis during squamous cell carcinoma formation in preputial gland duct. Int J Cancer 132:2065-75
Iqbal, Jameel; Sun, Li; Cao, Jay et al. (2013) Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Proc Natl Acad Sci U S A 110:11115-20
Dong, Hongbin; Shertzer, Howard G; Genter, Mary Beth et al. (2013) Mitochondrial targeting of mouse NQO1 and CYP1B1 proteins. Biochem Biophys Res Commun 435:727-32
Divanovic, Senad; Dalli, Jesmond; Jorge-Nebert, Lucia F et al. (2013) Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways. J Immunol 191:3347-57
Chen, Ying; Curran, Christine P; Nebert, Daniel W et al. (2012) Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm-/- knockout mice. Neurotoxicol Teratol 34:450-7
Chen, Y; Curran, C P; Nebert, D W et al. (2012) Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice. Genes Brain Behav 11:269-77

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