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.
Showing the most recent 10 out of 13 publications
