Cytochromes P45O constitute a family of chemical-metabolizing enzymes, the activities of which are major determinants of the biological effects of chemicals. Induction by chemicals (including acetone and pyridine) is among the mechanisms that regulate the activities of these enzymes. Acetone and pyridine are among the major constituents of cigarette smoke, are widely used as industrial solvents, and are prevalent in the environment. Acetone is known to induce cytochrome P450 form 2E1 (CYP2E1), whereas pyridine induces forms 1A1 (CYP1A1) and 1A2 (CYP1A2), in addition to CYP2E1. CYP1A1, CYP1A2 and CYP2E1 are highly active in bioactivating procarcinogens to cancer-initiating derivatives. The impetus for this proposal is our observation in preliminary studies that a combination of acetone and pyridine causes more than an additive induction of CYP1A1 and CYP1A2 in rat hepatic and extrahepatic tissues. Neither the induction of CYP1A1 and CYP1A2 by acetone nor the interactive effect of acetone and pyridine on the induction of any P450 isozymes has been hitherto described. The objective of this proposal is twofold: (i) to establish the mechanisms by which pyridine synergizes the induction by acetone of P450 in the kidney, liver and lung and (ii) to assess the health relevance of the induction. In studies to establish the mechanisms of P450 induction by acetone and pyridine, the role of transcription and post-transcriptional mechanisms (including mRNA stabilization, mRNA translation, and protein stabilization) will be examined. Studies to assess the health relevance of P450 induction by acetone and pyridine will include dose-induction response experiments. Being an inducer of P450 and a source of major health concern, cigarette smoke serves a good model source of acetone and pyridine for assessing the contribution of the two compounds to P450 induction in real life (such as cigarette smoke exposure). Studies to assess the contribution of acetone and pyridine to P450 induction by cigarette smoke will be performed in rats and in human lung specimens. In the rat studies, the P450 profile induced by (i) cigarette smoke and (ii) doses of acetone and pyridine found in cigarette smoke will be compared. In the human studies, the pulmonary P450 profile induced (i) in smokers and (ii) by acetone and pyridine in cultured explants will be compared. The results are expected to contribute to the understanding of the mechanisms of (i) P450 regulation and (ii) the biological effects of tobacco smoke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006414-04
Application #
2414970
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1994-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Iba, Michael M; Nguyen, Truyen; Fung, Jacqueline (2002) CYP1A1 induction by pyridine and its metabolites in HepG2 cells. Arch Biochem Biophys 404:326-34
Iba, M M; Fung, J (2001) Pulmonary Cyp1A1 and CYP1A2 levels and activities in adult male and female offspring of rats exposed during gestation and lactation to 2,3,7, 8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol 62:617-26
Wei, C; Caccavale, R J; Kehoe, J J et al. (2001) CYP1A2 is expressed along with CYP1A1 in the human lung. Cancer Lett 171:113-20
Iba, M M; Fung, J; Cooper, K R et al. (2000) Effect of gestational and lactational 2,3,7, 8-tetrachlorodibenzo-p-dioxin exposure on the level and catalytic activities of hepatic microsomal CYP1A in prepubertal and adult rats. Biochem Pharmacol 59:1147-54
Iba, M M; Fung, J; Giannone, J V et al. (2000) Comparative induction of CYP1A1 expression by pyridine and its metabolites. Arch Biochem Biophys 378:299-310
Iba, M M; Fung, J; Gonzalez, F J (2000) Functional Cyp2e1 is required for substantial in vivo formation of 2,5-hexanedione from n-hexane in the mouse. Arch Toxicol 74:582-6
Iba, M M; Fung, J; Thomas, P E et al. (1999) Constitutive and induced expression by pyridine and beta-naphthoflavone of rat CYP1A is sexually dimorphic. Arch Toxicol 73:208-16
Iba, M M; Fung, J (1999) Induction of pulmonary cytochrome P4501A1: interactive effects of nicotine and mecamylamine. Eur J Pharmacol 383:399-403
Fung, J; Thomas, P E; Iba, M M (1999) Cytochrome P450 1A1 in rat peripheral blood lymphocytes: inducibility in vivo and bioactivation of benzo[a]pyrene in the Salmonella typhimurium mutagenicity assay in vitro. Mutat Res 438:1-12

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