Malaiyandi Viba, Goodz Shari D, Sellers Edward M, Tyndale Rachel F
Department of Pharmacology, Center for Addiction and Mental Health, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Cancer Epidemiol Biomarkers Prev. 2006 Oct;15(10):1812-9. doi: 10.1158/1055-9965.EPI-05-0723.
CYP2A6 inactivates nicotine to cotinine and cotinine to 3-hydroxycotinine. We investigated which of plasma nicotine and metabolites were most related to CYP2A6 genotype and smoking levels. We assessed demographic and smoking histories in 152 Caucasian ad libitum smokers, measured breath carbon monoxide (CO) levels, and determined plasma nicotine, cotinine, and 3-hydroxycotinine by high-performance liquid chromatography and CYP2A6 genotypes by PCR. Cigarettes per day was most closely related to CO (r = 0.60, P < 0.001) followed by plasma cotinine (r = 0.53, P < 0.001), whereas plasma cotinine was most strongly correlated with CO levels (r = 0.74, P < 0.001), confirming that cotinine is a good indicator of smoking levels; this was not limited by CYP2A6 variants. 3-Hydroxycotinine/cotinine is reported to be a good marker of CYP2A6 activity, and we found that the 3-hydroxycotinine/(cotinine + nicotine) ratio was most correlated with CYP2A6 genotype (r = 0.38, P < 0.001). Inclusion of the CYP2A6*12A allele strengthened the correlation (r = 0.46, P < 0.001), suggesting that the identification of novel alleles will continue to improve this relationship. Nicotine metabolism is slower in smokers, and we have shown that CYP2A6 is reduced by nicotine treatment in monkeys. Here, we found that plasma nicotine levels were inversely correlated with CYP2A6 activity (3-hydroxycotinine/cotinine, r = -0.41, P < 0.001) among those without CYP2A6 variants, suggesting a reduction in metabolism with higher nicotine levels. Together, these findings (a) confirm the use of plasma cotinine and CO as indicators of Caucasians' smoking levels, and that this is not limited by CYP2A6 genetic variation; (b) indicate that 3-hydroxycotinine/cotinine and 3-hydroxycotinine/(cotinine + nicotine) are moderately good indicators of the CYP2A6 genotype; and (c) support that nicotine exposure may reduce its own metabolism.
细胞色素P450 2A6（CYP2A6）可将尼古丁转化为可替宁，将可替宁转化为3-羟基可替宁。我们研究了血浆中的尼古丁及其代谢产物中，哪些与CYP2A6基因型和吸烟水平最为相关。我们评估了152名随意吸烟者的人口统计学特征和吸烟史，测量了呼出气体中的一氧化碳（CO）水平，并通过高效液相色谱法测定了血浆中的尼古丁、可替宁和3-羟基可替宁，通过聚合酶链反应（PCR）测定了CYP2A6基因型。每日吸烟量与CO的相关性最为密切（r = 0.60，P < 0.001），其次是血浆可替宁（r = 0.53，P < 0.001），而血浆可替宁与CO水平的相关性最强（r = 0.74，P < 0.001），这证实了可替宁是吸烟水平的良好指标；这不受CYP2A6变异的限制。据报道，3-羟基可替宁/可替宁是CYP2A6活性的良好标志物，我们发现3-羟基可替宁/（可替宁 + 尼古丁）比值与CYP2A6基因型的相关性最强（r = 0.38，P < 0.001）。纳入CYP2A6*12A等位基因可增强这种相关性（r = 0.46，P < 0.001），这表明鉴定新的等位基因将继续改善这种关系。吸烟者体内尼古丁代谢较慢，我们已经表明，尼古丁处理可使猴子体内的CYP2A6减少。在此，我们发现，在没有CYP2A6变异的人群中，血浆尼古丁水平与CYP2A6活性（3-羟基可替宁/可替宁，r = -0.41，P < 0.001）呈负相关，这表明尼古丁水平较高时代谢会降低。总之，这些发现（a）证实了血浆可替宁和CO可作为白种人吸烟水平的指标，且这不受CYP2A6基因变异的限制；（b）表明3-羟基可替宁/可替宁和3-羟基可替宁/（可替宁 + 尼古丁）是CYP2A6基因型的中度良好指标；（c）支持尼古丁暴露可能会降低其自身代谢。
