| The hypothesis of this dissertation is that members of CYP2A subfamily of cytochrome P450 monooxygenases are expressed predominantly in the respiratory tract in humans and in mammalian animals, where they play important roles in the metabolic activation and toxicity of environmental chemicals. Furthermore, the expression of these enzymes may be inducible in human tissues by xenobiotic compounds, which lead to enhanced capacity for metabolic activation of procarcinogens and other toxicants. Nasal predominant expression of CYP2A3 and CYP2A5 was demonstrated in rats and mice, respectively. In humans, the expression of CYP2A6 was detected in the nasal mucosa, and the mRNA for CYP2A13, a newly identified CYP2A, was found to be expressed predominantly in the nasal mucosa, lung, and trachea.;A CYP2A13 cDNA was obtained from human nasal mucosa. In a reconstituted system, heterologously expressed CYP2A13 was highly active in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, with a catalytic efficiency much greater than that of other human P450s examined previously. These findings indicate, for the first time, that CYP2A13 is functional and that it may play important roles in tobacco-related tumorigenesis in the respiratory tract.;The xenobiotic inducibility of the CYP2As was examined in mice. Pyrazole, which is known to induce CYP2A5 in mouse liver, did not cause a significant induction of CYP2A4/5 in either olfactory mucosa or lung. The lack of CYP2A4/5 induction in the olfactory mucosa was also observed for several other known inducers of hepatic CYP2A5, including cobaltous chloride, stannous chloride, griseofulvin, thioacetamide, and aminotriazole. Thus, the mechanism of CYP2A5 induction, which involves post-transcriptional events, is tissue-specific.;To assess the hepatic inducibility of human CYP2A6, a novel transgenic mouse model carrying a CYP2A6 cDNA was generated. Expression of the transgene, which was under the control of the mouse transthyretin promoter/enhancer, was detected predominantly in the liver. Pyrazole treatment induced CYP2A6 protein, but not CYP2A6-dependent coumarin 7-hydroxylase activity, whereas cobaltous chloride and stannous chloride induced both in transgenic mouse liver. These results suggest that human CYP2A6 may also be inducible by known CYP2A5 inducers. |
