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)