Chemistry:Menthofuran
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 in plants such as peppermint from pulegone by the enzyme menthofuran synthase.[3]
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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.[4]
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.[5][6][7][8]
Menthofuran may deplete glutathione levels, leaving hepatocytes vulnerable to free radical damage.[6]
References
- ↑ "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. doi:10.7326/0003-4819-124-8-199604150-00004. PMID 8633832.
- ↑ "Reactive intermediates in the oxidation of menthofuran by cytochromes P-450". Chemical Research in Toxicology 5 (1): 123–30. 1992. doi:10.1021/tx00025a021. PMID 1581528.
- ↑ "Menthofuran regulates essential oil biosynthesis in peppermint by controlling a downstream monoterpene reductase". Proceedings of the National Academy of Sciences of the United States of America 100 (24): 14481–6. November 2003. doi:10.1073/pnas.2436325100. PMID 14623962. Bibcode: 2003PNAS..10014481M.
- ↑ Mariko Aso; Sakamoto, Mizue; Urakawa, Narumi; Kanematsu, Ken (1990). "Furannulation strategy. An efficient synthesis of fused 3-methylfurans". Heterocycles 31 (6): 1003–6. doi:10.3987/com-90-5392.
- ↑ Khojasteh-Bakh, S. C.; Koenigs, L. L.; Peter, R. M.; Trager, W. F.; Nelson, S. D. (July 1998). "(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6". Drug Metabolism and Disposition 26 (7): 701–704. PMID 9660853.
- ↑ 6.0 6.1 Gordon, W. P.; Huitric, A. C.; Seth, C. L.; McClanahan, R. H.; Nelson, S. D. (February 26, 1989). "The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofuran". Drug Metabolism and Disposition 15 (5): 589–594. doi:10.1016/S0090-9556(25)06790-X. PMID 2891472.
- ↑ Thomassen, D.; Pearson, P. G.; Slattery, J. T.; Nelson, S. D. (January 17, 1991). "Partial characterization of biliary metabolites of pulegone by tandem mass spectrometry. Detection of glucuronide, glutathione, and glutathionyl glucuronide conjugates.". Drug Metabolism and Disposition 19 (5): 997–104. doi:10.1016/S0090-9556(25)08983-4. PMID 1686249.
- ↑ "Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, β-nicotyrine and menthol". Chemico-Biological Interactions 197 (2–3): 87–92. May 2012. doi:10.1016/j.cbi.2012.03.009. PMID 22486895. Bibcode: 2012CBI...197...87K.
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