Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes
Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes
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DOI：
10.1124/dmd.107.017343
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发表时间：
2007-11
影响因子：
3.9
通讯作者：
Pamela J Brown;L. Bedard;K. Reid;D. Petsikas;T. Massey
中科院分区：
文献类型：
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作者：
Pamela J Brown;L. Bedard;K. Reid;D. Petsikas;T. Massey
本研究的目的是研究细胞色素P450酶A13和细胞色素P450酶A6在人外周肺微粒体中对4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone代谢的影响，以及基因多态性对NNK代谢的影响。NNK的酮基还原代谢物4-(甲基亚硝基)-1-(3-吡啶)-1-丁醇(NNAL)是NNK的主要代谢产物，其含量在0.28~0.9%/mg蛋白/min之间。根据α-碳羟化对NNK和NNAL的总生物活性，可将受试者分为高(17例)和低(12例)生物激活剂[(5.2 6±1.2 3)×10-2和(6.49±5.90)×10-3%总α-羟化/mg蛋白/分钟，P<0.0 5]。然而，细胞色素P450 2A13mRNA与总的NNK和NNAL的α羟化和NNAL-N-氧化物的形成相关(P<；005)。NNAL的形成程度与细胞色素P4502A13mRNA的表达呈正相关(P<；0.05)。对84例受试者进行了CYP2A13 Arg257Cys多态基因分型，其中一个变异(Arg/Cys)的NNK代谢与其他受试者相似。尽管研究结果并不支持所有个体外周肺中的NNK生物激活和解毒的主要贡献者是细胞色素P450 2A13或细胞色素P450 2 A6，但在某些个体中，细胞色素P450 2 A13可能是重要的。
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.