Variation in trans-3'-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake.
Variation in trans-3'-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake.
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DOI：
10.1371/journal.pone.0070938
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
Zhu AZ;Zhou Q;Cox LS;Ahluwalia JS;Benowitz NL;Tyndale RF
细胞色素P450 2A6将尼古丁代谢成其主要代谢物可替宁，并介导可替宁代谢成反式-3‘-羟基可替宁(3HC)。3HC与可替宁的比值(“尼古丁代谢物比率”，简称核磁共振)是衡量细胞色素P4502A6介导的尼古丁代谢率和尼古丁总清除量的体内标志物，并与多种吸烟行为的差异有关。影响核磁共振的3HC的清除通过UGT2B17和可能的UGT2B10的肾脏排泄和代谢发生为3HC-葡萄糖醛酸苷。我们调查了较慢的3HC葡萄糖醛酸化反应是否会改变核磁共振，改变其预测CYP2A6活性的能力，并降低其临床应用价值。对540例非裔美国吸烟者进行了血浆核磁共振、3种尿液NMR、3种尿液3HC糖醛酸化反应表型和总尼古丁等价物的检测。对UGT2B17基因缺失和UGT2B10*2进行基因分型。UGT2B17基因缺失，而不是UGT2B10*2，与较慢的3HC-葡萄糖醛酸化反应相关(由三种3HC-葡萄糖醛酸化表型指示)，表明它在这一葡萄糖醛酸化途径中起作用。然而，较低的3HC葡萄糖醛酸化或UGT2B17和UGT2B10的存在都不会减少功能等位基因，改变血浆或尿液NMR或吸烟水平。3HC葡萄糖醛酸化活性的变化，包括由UGT2B17基因缺失引起的变化，没有显著改变核磁共振，因此不太可能影响核磁共振在吸烟行为和戒烟研究中的临床应用。这项研究表明，核磁共振不会因3HC葡萄糖醛酸化速率的差异而改变，这进一步支持了核磁共振是CYP2A6介导的尼古丁代谢的可靠指标。
CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the “nicotine metabolite ratio”, NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility. Plasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped. The UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking. Variation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism.
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DOI：
10.1093/jnci/94.2.108
发表时间：
2002-01-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Benowitz, NL;Pérez-Stable, EJ;Jacob, P
通讯作者：
Jacob, P
尼古丁代谢物比预测吸烟地形和致癌生物标志物水平。
DOI：
10.1158/1055-9965.epi-10-0674
发表时间：
2011-02
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Strasser AA;Benowitz NL;Pinto AG;Tang KZ;Hecht SS;Carmella SG;Tyndale RF;Lerman CE
通讯作者：
Lerman CE
影响因子：
11.2
作者：
Chen, Gang;Blevins-Primeau, Andrea S.;Lazarus, Philip
通讯作者：
Lazarus, Philip
DOI：
10.1124/jpet.109.159855
发表时间：
2010-01-01
影响因子：
3.5
作者：
Berg, Jeannette Zinggeler;Mason, Jesse;Murphy, Sharon E.
通讯作者：
Murphy, Sharon E.
影响因子：
6.7
作者：
BENOWITZ, NL;JACOB, P
通讯作者：
JACOB, P