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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specificnitrosamine in animals and has been suggested to play a role in humantobacco-related cancers. Our previous study demonstrated that cytochrome P450(P450) 1A2 catalyzes the formation of 4-hydroxy-1-(3-pyridyl)-1-butanone (ketoalcohol) (an α-hydroxylation product) from NNK in human liver microsomes.Phenethyl isothiocyanate (PEITC) inhibits NNK tumorigenesis by blocking theactivation of NNK. The purpose of the present study was to elucidate themechanism of inhibition of P450 1A2-catalyzed NNK activation by PEITC. HumanP450 1A2 was expressed in  Escherichia coli  and purified tohomogeneity. In a reconstituted system, P450 1A2 catalyzed the formation of ketoalcohol and 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde) from NNK, with theketo alcohol being the major metabolite. The apparent  K m andV  max  values for keto alcohol formation was 380μM and 1.7 nmol/min/nmol P450, respectively. For thetobacco-specific nitrosamine  N -nitrosonornicotine (NNN), P4501A2 catalyzed the formation of the derived 4-hydroxy-4-(3-pyridyl)butyric acid(hydroxy acid), 4-oxo-4-(3-pyridyl)butyric acid (keto acid) and keto alcohol. Incomparison to NNK, NNNhad a lower rate of oxidation with P450 1A2. PEITCdecreased the formation of the NNK-derived keto alcohol in aconcentration-dependent manner, with an IC 50  value of 0.14 μM.PEITC was a competitive inhibitor of P450 1A2, exhibiting aK  i  value of 0.18 μM. Preincubation ofPEITC with NADPH in the reconstituted system resulted in a further decrease(25%) in the catalytic activity of P450 1A2, suggesting that there is aslow metabolism-dependent inhibition of P450 1A2 by PEITC. The formation of ketoaldehyde and keto alcohol was inhibited by PEITCin human liver microsomes withIC 50  values of 9.5 and 4.6 μM respectively.Methoxyresorufin  O -dealkylase activity, a marker for P450 1A2,was decreased by PEITC in a concentration-dependent manner, with anIC 50  of 0.34 μM. The results suggest that PEITC itself isa potent inhibitor of P450 1A2 and that a metabolite(s) of PEITC can alsoinhibit P450 1A2. We conclude that PEITC may be an effective inhibitor of thecarcinogenicity or toxicity of chemicals that are activated by P450 1A2.

carcinogenesis

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by                     human cytochrome P450 1A2 and its inhibition by phenethyl                     isothiocyanate