Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes

The objectives of this study were to determine the contributions of CYP2A13 and CYP2A6 to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human peripheral lung microsomes and to determine the influence of the genetic polymorphism, CYP2A13 Arg257Cys, on NNK metabolism. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the keto-reduced metabolite of NNK, was the major metabolite produced, ranging from 0.28 to 0.9%/mg protein/min. Based on total bioactivation of NNK and NNAL by α-carbon hydroxylation, subjects could be classified as either high (17 subjects) or low (12 subjects) bioactivators [(5.26 ± 1.23) × 10-2 and (6.49 ± 5.90) × 10-3% total α-hydroxylation/mg protein/min, P 0.05). However, subgroups of individuals were identified for whom CYP2A13 mRNA correlated with total NNK and NNAL α-hydroxylation and NNAL- N -oxide formation ( P < 0.05). The degree of NNAL formation and CYP2A13 mRNA was also correlated ( P < 0.05). Subjects ( n = 84) were genotyped for the CYP2A13 Arg257Cys polymorphism, and NNK metabolism for the one variant (Arg/Cys) was similar to that for other subjects. Although results do not support CYP2A13 or CYP2A6 as predominant contributors to NNK bioactivation and detoxification in peripheral lung of all individuals, CYP2A13 may be important in some.