MacDougall James M, Fandrick Keith, Zhang Xiaodong, Serafin Scott V, Cashman John R
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92126, USA.
Chem Res Toxicol. 2003 Aug;16(8):988-93. doi: 10.1021/tx0340551.
(-)-Menthol is a widely used flavoring ingredient present in mouthwash, foods, toothpaste, and cigarettes; yet, the pharmacological effects of menthol have not been widely studied. Mentholated cigarette smoking may increase the risk for lung cancer. Many African American smokers smoke mentholated cigarettes, and African Americans have a significantly higher incidence of lung cancer as compared with whites. There may be a relationship between the incidence of lung cancer and the type of cigarette smoked because the use of mentholated cigarettes by white smokers is significantly less and the incidence of lung cancer is less. The mechanism whereby (-)-menthol could increase the health risk of smoking is not known. The results of our in vitro studies herein show that (-)-menthol and synthetic congeners inhibit the microsomal oxidation of nicotine to cotinine and the P450 2A6-mediated 7-hydroxylation of coumarin. Replacement of the alcohol oxygen atom of menthol with other heteroatoms increased the potency of P450 2A6 inhibition. Thus, the K(i) value of (-)-menthol for inhibition of microsomal nicotine oxidation was 69.7 micro M but neomenthyl thiol possesses a K(i) value of 13.8 micro M. Menthylamine inhibited nicotine oxidation with a K(i) value of 49.8 micro M, but its hydroxylamine derivative gave an IC(50) value of 2.2 micro M. A series of 16 menthol derivatives and putative metabolites were procured or chemically synthesized and tested as inhibitors of P450 2A6. While highly potent inhibition of P450 2A6 was not observed for the menthol analogues examined, it is nevertheless possible that smoking mentholated cigarettes leads to inhibition of nicotine metabolism and allows the smoker to achieve a certain elevated dose of nicotine each day. This may be another example of self-medication to obtain the desired effect of nicotine.
（-）-薄荷醇是一种广泛用于漱口水、食品、牙膏和香烟中的调味成分；然而，薄荷醇的药理作用尚未得到广泛研究。吸含薄荷醇的香烟可能会增加患肺癌的风险。许多非裔美国吸烟者吸含薄荷醇的香烟，与白人相比，非裔美国人患肺癌的发病率显著更高。肺癌发病率与所吸香烟类型之间可能存在关联，因为白人吸烟者使用含薄荷醇香烟的比例显著较低，且肺癌发病率也较低。（-）-薄荷醇增加吸烟健康风险的机制尚不清楚。我们在此的体外研究结果表明，（-）-薄荷醇及其合成同系物可抑制微粒体将尼古丁氧化为可替宁以及细胞色素P450 2A6介导的香豆素7-羟基化。用其他杂原子取代薄荷醇的醇氧原子可增强对细胞色素P450 2A6的抑制效力。因此，（-）-薄荷醇抑制微粒体尼古丁氧化的K（i）值为69.7微摩尔，但新薄荷基硫醇的K（i）值为13.8微摩尔。薄荷胺抑制尼古丁氧化的K（i）值为49.8微摩尔，但其羟胺衍生物的IC（50）值为2.2微摩尔。我们获取或化学合成了一系列16种薄荷醇衍生物及假定代谢物，并将其作为细胞色素P450 2A6的抑制剂进行测试。虽然在所检测的薄荷醇类似物中未观察到对细胞色素P450 2A6的高效抑制，但吸含薄荷醇的香烟仍有可能导致尼古丁代谢受到抑制，并使吸烟者每天能够达到一定的尼古丁升高剂量。这可能是自我用药以获得所需尼古丁效果的另一个例子。
