Fig 1.
Metabolic pathway of menthol in rats and in human.
This pathway is an adaptation from Yamaguchi, Caldwell, & Farmer [17], Madyastha & Sirvastan [18] and Hiki et al. [19]. Red, Green, and Blue numbers indicate that menthol metabolites were found in both rats and human, only in rats, and only in human respectively. Gray and Black numbers indicate menthol metabolites proposed by previous experiments and by this paper respectively. Arrows to the right and arrows upward indicate oxidation reactions + O2 and–H2 respectively. Downward arrows indicate conjugation with sulfate. Dashed arrows indicate reactions of four-membered ring metabolites. Diagonal arrows toward top left indicate dehydration reaction. Main pathways are shown on the left and pathways containing glucuronide metabolites with similar possible connections are shown on the right. Lists of compounds and reactions are provided in S1 Table and Fig 3, respectively.
Fig 2.
Abbreviation system for menthol metabolites in this study.
Abbreviations and a list of all 102 compounds in this study grouped by molecular formula are provided in S1 Table.
Fig 3.
Abbreviation system for reactions of menthol metabolites in this study.
Fig 4.
Average Gibbs energies of reaction in the gas phase and in solution for various reactions.
Energies were obtained at the B3LYP/6-311++G(d,p) level of theory for each reaction: (o1) oxidation from alkane to alcohol, (o2) oxidation from aldehyde to carboxylic acid, (o3) oxidation from alcohol to aldehyde, (4D) dehydration or four-membered ring formation, (5A) aldol reaction or five-membered ring formation, (g) conjugation with glucuronic acid and (s) conjugation with sulfate at five different positions of (-)-menthol. Representative reactions of each type are shown in Fig 3.
Fig 5.
Relative stability of 102 (-)-menthol metabolite compounds at the B3LYP/6-311++G(d,p) level of theory.
Fig 6.
Lowest Gibbs energy diagram for the metabolism of (-)-menthol at the B3LYP/6-311++G(d,p) level of theory.