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Mechanisms of Inhibition of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Bioactivation in Mouse by Dietary Phenethyl Isothiocyanate¹

Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855-0789

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induces lung tumors in mice, rats, and hamsters. Phenethyl isothiocyanate (PEITC), which occurs as gluconasturtlin in cruciferous vegetables, is a potent inhibitor of NNK-induced carcinogenesis. The present study investigated the enzymatic basis for the bioactivation of NNK and the mechanisms of the inhibition of this process by dietary PEITC in mice. The apparent K_m for the formation of keto aldehyde, keto alcohol, and NNK-N-oxide in lung microsomes was 4.9, 2.6, and 1.8 µM and, in liver microsomes, 5.5, 5.1, and 8.8 µM, respectively. Immunoinhibition studies suggested that cytochrome P450s (P450s) 2A1 and 2B1 or related forms are the major enzymes involved in the oxidative metabolism of NNK in mouse lung microsomes. When female A/J mice were fed diets containing 0, 1, or 3 µmol of PEITC/g of diet for 4 wk, the dietary PEITC had no significant effects on the food consumption and body weight of the mice. NNK oxidation in the lung microsomes of mice consuming the 1 or 3 µmol of PEITC/g of diet was decreased by 13 to 27% or 30 to 50%, respectively. In liver microsomes, whose NNK oxidative metabolism rates were about twice those of lung microsomes on a per mg of protein basis, the activities were decreased by 14 to 31% by the 3 µmol of PEITC/g of diet. The apparent K_m remained unchanged, and the apparent V_max decreased in the lung and liver microsomes of PEITC-fed mice, suggesting a noncompetitive nature of the inhibition. When added to the incubation mixture, PEITC decreased NNK metabolism in a concentration-dependent manner and exhibited a competitive inhibition with apparent K_i values of 51 to 93 nM. Dietary PEITC decreased the hepatic P450 content by 25%, but increased (2-fold) the O-dealkylase activities of 7-pentoxyresorufin (indicative of P450 2B1) and 7-ethoxyresorufin (indicative of P450 1A) in the liver microsomes of mice consuming the 3 µmol of PEITC/g of diet. The P450 2B level was increased in liver microsomes but slightly decreased in the lung microsomes. The P450 2E1 level was increased by dietary PEITC by 1.2- and 1.6-fold in the liver and lung microsomes, respectively. The activities of glutathione S-transferase and NAD(P)H-quinone oxidoreductase in liver and lung microsomes were not affected appreciably by the dietary PEITC treatment. The results suggest that chronic consumption of PEITC decreases the rate of metabolic activation of NNK by chemical inactivation and competitive inhibition of the enzyme(s) responsible for NNK oxidation.

¹ This study was supported by NIH Grants CA-46535 and CA-37037 and by National Institute of Environmental Health Sciences Center Grant ES-05022.

² To whom requests for reprints should be addressed.

Received 12/17/92. Accepted 5/ 6/93.

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