Induction of N-nitrosodimethylamine metabolism in liver and lung by in vivo pyridine treatments of rabbits.
N-Nitrosodimethylamine is a procarcinogen that is activated by cytochrome P450 dependent N-nitrosodimethylamine N-demethylase to labile alpha-carbon hydroxylated products further resulting in active methylating agents. In vivo intraperitoneal administration of pyridine to rabbits significantly increased N-nitrosodimethylamine N-demethylase activity by 6.9- and 5.2-fold in liver and lung microsomes, respectively. Although, p-nitrophenol hydroxylase and aniline 4-hydroxylase activities were markedly enhanced by pyridine treatment in liver about 4.4- and 5.8-fold, respectively, no change was observed in the activities of these enzymes in lung microsomes. Pyridine treatment also elevated P450 contents of liver and lung by 2.04- and 1.4-fold, respectively. SDS-PAGE of pyridine-induced liver microsomes revealed a protein band of enhanced intensity having Mr of 51,000 migrating in the region of cytochrome P4502E1. The results obtained in this study demonstrated for the first time, a significant 5.2-fold induction of NDMA N-demethylase activity in the rabbit lung over the controls. Pyridine is readily absorbed by inhalation and is a constituent of tobacco and tobacco smoke. Thus induction of NDMA N-demethylase suggests that in the lung, as in the liver, pyridine may stimulate the metabolic activation of this nitrosamine significantly.
Arinç
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Department of Biological Sciences, Middle East Technical University, Ankara, Turkey. earinc@metu.edu.tr
Adali
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Gençler-Ozkan
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AM
D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits
D002273:Carcinogens; D011725:Pyridines; D019392:Cytochrome P-450 CYP2E1; D000815:Aniline Hydroxylase; D004128:Dimethylnitrosamine; C023666:pyridine