Inhibition of human Liver Microsomal (S)-Nicotine Oxidation by (−)-Menthol and analogues

Introduction:
This text provides an in-depth analysis of the effects of menthol, a widely used flavoring ingredient, on the microsomal oxidation of nicotine and the P450 2a6-mediated 7-hydroxylation of coumarin. The study also explores the inhibitory potential of various menthol analogues on these processes.

Key Points:

* Menthol inhibits human liver microsomal nicotine oxidation and P450 2a6-mediated coumarin 7-hydroxylase.
* Replacement of the alcohol oxygen atom of menthol with other heteroatoms increases the potency of P450 2a6 inhibition.
* a series of 16 menthol derivatives and putative metabolites were tested as inhibitors of P450 2a6, with varying degrees of inhibition observed.
* The more nucleophilic heteroatom-containing menthol analogues have the greatest inhibitory potency, consistent with the P450 2a6 prosthetic group as the site of inhibition.
* In mentholated cigarettes, the increased plasma area under the curve for nicotine and tobacco-related chemicals may contribute to the increased health risks associated with smoking mentholated cigarettes.
* The study highlights the potential impact of menthol on nicotine metabolism and its implications for smoking behavior and health risks.

Main Message:
The text emphasizes the inhibitory effects of menthol on nicotine oxidation and P450 2a6-mediated processes, suggesting that menthol may contribute to increased health risks associated with smoking mentholated cigarettes. The study underscores the importance of understanding the pharmacological effects of menthol and its analogues, particularly in the context of smoking behavior and tobacco regulation.

MacDougall, James M., Keith Fandrick, Xiaodong Zhang, Scott V. Serafin, and John R. Cashman. “Inhibition of human Liver Microsomal ( S )-Nicotine Oxidation by (−)-Menthol and analogues.” Chemical Research in Toxicology 16, no. 8 (august 1, 2003): 988–93. https://doi.org/10.1021/tx0340551.