Inhibition of Human Liver Microsomal (S)-Nicotine Oxidation by (−)-Menthol and Analogues

Abstract

(-)-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.

Metabolism and Disposition Kinetics of Nicotine

“…Menthol cigarette smoking has been associated with longer cotinine halflife in women (Ahijevych et al, 2002). Recently, a moderate inhibition of CYP2A6-mediated nicotine metabolism in human liver microsomes by menthol and various related compounds was reported (MacDougall et al, 2003). This is supported by a crossover study in people, showing that mentholated cigarette smoking significantly inhibits metabolism of nicotine to cotinine and nicotine glucuronidation when compared with smoking nonmentholated cigarettes (Benowitz et al, 2004a).…”

“…Inhibitors. Several compounds are inhibitors of CYP2A6-mediated nicotine metabolism in vitro, including methoxsalen (8-methoxypsoralen), tranylcypromine, tryptamine, coumarin, and neomenthyl thiol (Nakajima et al, 1996b;Zhang et al, 2001;Le Gal et al, 2003;MacDougall et al, 2003). Other inhibitors of coumarin 7-hydroxylation such as pilocarpine, metyrapone, R-(ϩ)-menthofuran, ␤-nicotyrine, naphthalene, 4,4Ј-dipyridyl disulfide, 2-(p-tolyl)-ethylamine, nootkatone, several azole antifungals, and rifampicin would also be expected to inhibit nicotine C-oxidation Tassaneeyakul et al, 2000;Fujita and Kamataki, 2001;Xia et al, 2002;Asikainen et al, 2003;Rahnasto et al, 2003;Denton et al, 2004).…”

Nicotine Metabolism in Young Adult Daily Menthol and Nonmenthol Smokers

“…Studies suggest that menthol inhibits the metabolism of nicotine in liver microsomal test systems 14 and influences the total metabolic clearance of nicotine. 15 Nicotine metabolism is primarily mediated by the enzyme cytochrome P450 2A6 (CYP2A6) in the liver.…”

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

“…Previously, isoflavones (Nakajima et al, 2006), menthol (MacDougall et al, 2003;Kramlinger et al, 2012), menthofuran (Khojasteh-Bakht et al, 1998), isothiocyanates (Nakajima et al, 2001;von Weymarn et al, 2007), and several others (Di et al, 2009) were studied and found to inhibit CYP2A6. Based on the structural and biophysical studies of CYP2A6, low-molecular-weight phenylpropanoids, such as t-CA (Fig.…”