Abstract
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]. Similarly, for detoxification, subjects could be grouped into high (9 subjects) and low (20 subjects) categories [(2.03 ± 1.65) × 10-3 and (2.50 ± 3.04) × 10-4% total N-oxidation/mg protein/min, P < 0.05]. When examining data from all individuals, no significant correlations were found between levels of CYP2A mRNA, CYP2A enzyme activity, or CYP2A immunoinhibition and the degree of total NNK bioactivation or detoxification (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.
Footnotes
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This work was supported by Canadian Institutes of Health Research Grant MT10382.
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doi:10.1124/dmd.107.017343.
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ABBREVIATIONS: NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNK-N-oxide, 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanone; NNAL-N-oxide, 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanol; keto alcohol, 4-hydroxy-1-(3-pyridyl)-1-butanone; diol, 1-(3-pyridyl)-1,4-butane diol; keto acid, 1-(3-pyridyl)-1-butanone-4-carboxylic acid; hydroxy acid, 1-(3-pyridyl)-1-butanol-4-carboxylic acid; P450, cytochrome P450; CO, carbon monoxide; RT-PCR, reverse transcription-polymerase chain reaction; CI, confidence interval.
- Received June 20, 2007.
- Accepted August 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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