Effects of pregnancy and ethanol treatment on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by hamster liver and lung microsomes.
The tobacco-specific N-nitrosamino 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in adult Syrian golden hamsters and causes a high incidence of tumors in the offspring of hamsters after in utero exposure. We have investigated how pregnancy and/or ethanol treatment modulates the microsomal metabolism of NNK. Pregnancy decreased the alpha-carbon hydroxylation (activation) of NNK, whereas it increased both the pyridine N-oxidation and carbonyl reduction of NNK in liver microsomes, but not in the lung. Ethanol treatment of nonpregnant hamsters induced both the hepatic microsomal alpha-carbon hydroxylation and pyridine N-oxidation of NNK, but it increased only the formation of NNAL, the N-nitroso alcohol NNAL, in the lung. Ethanol-consuming pregnant hamsters showed no changes in the hepatic or pulmonary metabolism of NNK. In contrast, fetal hamsters exposed in utero to ethanol showed a general increase in the rate of metabolism of NNK. Immunoblot analyses demonstrated a reduction in the P-450IIE1 and total P450IIB1/IIB2 protein levels in the liver of pregnant hamsters, whereas a moderate increase of P-450IIB1 was observed in the lung. Moreover, ethanol treatment increased the amount of immunodetectable P-450IIE1 and total P-450IIB1/IIB2 in the liver of nonpregnant hamsters, but only the hepatic P-450IIE1 was induced by ethanol in pregnant hamsters. The P-450IIB1 protein levels were not affected by ethanol treatment in the lung of nonpregnant, pregnant, or fetal hamsters. In contrast, the fetal hepatic P-450IIE1 and P-450IIB1/IIB2 protein levels were increased by transplacental ethanol exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada.
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Jorquera
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Castonguay
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Schuller
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D008168:Lung / Q000378:metabolism*; D008647:Mesocricetus; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*
D002273:Carcinogens; D009602:Nitrosamines; D000431:Ethanol; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System