Polycyclic aromatic hydrocarbons (PAHs), nitrosamines, and N-heterocyclics are present in combustion products, e.g. grilled foods &cigarette smoke. Cytochromes P450 1A1 &1B1 (CYP1A1, CYP1B1) are responsible for the metabolism of numerous PAHs, the prototype of which is benzo[a]pyrene (BaP). CYP1A2 is responsible for metabolizing nitrosamines and N-heterocyclics, but also PAHs (in particular, BaP) to a lesser extent. Using Cyp1a1(-/-) and Cyp1b1(-/-) knockout mice, we have shown that CYP1A1 is more important in detoxication than metabolic activation, whereas CYP1B1 causes metabolic activation of BaP to unwanted reactive intermediates. In other words, CYP1A1 is more good than bad in the intact mouse ingesting BaP, and CYP1B1 is more bad than good in the intact mouse administered PAHs by various routes. The importance of mesenteric lymphatics vs. the portal system (mesenteric blood vessels, liver, bile) is not known for oral BaP. This lab now has seven-all three single, all three double, and the one triple-Cyp1 knockout mouse lines. Our hypothesis is: lymph BaP uptake and CYP1B1 in distal tissues (e.g. immune cells, spleen, and bone marrow) are the principal causes of oral BaP toxicity, whereas inducible CYP1A1 in liver and intestine is the principal cause of BaP detoxication. In this proposed project, we therefore will: [a] identify and determine the amounts of metabolites vs. unchanged parent BaP in mesenteric lymph, portal vein blood, liver, and bile in wild-type and all seven Cyp1 knockout mouse lines, and the role and mechanism of chylomicrons in delivering BaP to target organs;[b] generate liver- and intestinal epithelium-specific Cyp1a1 conditional knockout lines;[c] replace the Cyp1b1 gene (in the genome) with the Cyp1a1 gene, and vice versa;and [d] repeat our BaP pharmacokinetics studies (see [a]) in these four newly generated mouse lines. Understanding the tissue- specific roles for each of the three CYP1 enzymes in the intact mouse receiving oral BaP will provide us with a greater understanding of BaP detoxification vs. metabolic activation. We expect this knowledge will provide a blueprint for understanding the mechanisms of elimination vs. dissemination of ingested BaP and will be informative in clinical studies in which we would determine which haplotypes of these three human genes might be associated with resistance vs. sensitivity to PAH-induced toxicity and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014403-04
Application #
7565952
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Thompson, Claudia L
Project Start
2006-02-17
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2009
Total Cost
$337,376
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Uno, Shigeyuki; Nebert, Daniel W; Makishima, Makoto (2018) Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice. Food Chem Toxicol 113:73-82
Schiering, Chris; Wincent, Emma; Metidji, Amina et al. (2017) Feedback control of AHR signalling regulates intestinal immunity. Nature 542:242-245
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

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