Menthofuran Explained

Menthofuran is an organic compound found in a variety of essential oils including that of pennyroyal (Mentha pulegium). It is highly toxic and believed to be the primary toxin in pennyroyal responsible for its potentially fatal effects.^[1] After ingestion of menthofuran, it is metabolically activated to chemically reactive intermediates that are hepatotoxic.^[2]

Biosynthesis

Menthofuran is produced biosynthetically from pulegone by the enzyme menthofuran synthase.

Chemistry

Synthesis

Menthofuran can be synthesized from 5-methylcyclohexane-1,3-dione and allenyldimethylsulfonium bromide in two steps via a furannulation strategy consisting of enolate addition and rearrangement.^[3]

Pharmacology

Menthofuran is a metabolite of pulegone. Both in vitro and in vivo studies have found the pulegone metabolite menthofuran to be an inhibitor of CYP2A6.^{[4] [5] [6] [7]}

Menthofuran may deplete glutathione levels, leaving hepatocytes vulnerable to free radical damage.^[5]

Notes and References

1. Anderson IB, Mullen WH, Meeker JE, Khojasteh-BakhtSC, Oishi S, Nelson SD, Blanc PD . Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature . Annals of Internal Medicine . 124 . 8 . 726–34 . April 1996 . 8633832 . 10.7326/0003-4819-124-8-199604150-00004. 24375611 .
2. Thomassen D, Knebel N, Slattery JT, McClanahan RH, Nelson SD . Reactive intermediates in the oxidation of menthofuran by cytochromes P-450 . Chemical Research in Toxicology . 5 . 1 . 123–30 . 1992 . 1581528 . 10.1021/tx00025a021.
3. Mariko Aso. Furannulation strategy. An efficient synthesis of fused 3-methylfurans. Heterocycles. 31 . 6. 1003–6. 1990. Sakamoto. Mizue. Urakawa. Narumi. Kanematsu. Ken. 10.3987/com-90-5392. 2024-02-17. free.
4. Khojasteh-Bakh. S. C.. Koenigs. L. L.. Peter. R. M.. Trager. W. F.. Nelson. S. D.. (R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6. Drug Metabolism and Disposition. July 1998. 26. 7. 701–704. 9660853.
5. Gordon. W. P.. Huitric. A. C.. Seth. C. L.. McClanahan. R. H.. Nelson. S. D.. The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofuran. Drug Metabolism and Disposition. February 26, 1989. 15. 5. 589–594. 2891472.
6. Thomassen. D.. Pearson. P. G.. Slattery. J. T.. Nelson. S. D.. Partial characterization of biliary metabolites of pulegone by tandem mass spectrometry. Detection of glucuronide, glutathione, and glutathionyl glucuronide conjugates.. Drug Metabolism and Disposition. January 17, 1991. 19. 5. 997–104. 1686249.
7. Kramlinger VM, von Weymarn LB, Murphy SE . Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, β-nicotyrine and menthol . . 197 . 2–3 . 87–92 . May 2012 . 22486895 . 3362486 . 10.1016/j.cbi.2012.03.009 . 2012CBI...197...87K .