Menthofuran

Menthofuran
Names
IUPAC name
3,6-Dimethyl-4,5,6,7-tetrahydro-1-benzofuran
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.007.087 Edit this at Wikidata
UNII
  • InChI=1S/C10H14O/c1-7-3-4-9-8(2)6-11-10(9)5-7/h6-7H,3-5H2,1-2H3
    Key: YGWKXXYGDYYFJU-UHFFFAOYSA-N
  • InChI=1/C10H14O/c1-7-3-4-9-8(2)6-11-10(9)5-7/h6-7H,3-5H2,1-2H3
    Key: YGWKXXYGDYYFJU-UHFFFAOYAW
  • o1c2c(c(c1)C)CCC(C2)C
Properties
C10H14O
Molar mass 150.221 g·mol−1
Boiling point 208
Hazards
Flash point 86
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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]

2D representation of the chemical structure of pulegone .
pulegone
 
O2
2 H2O
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right
 
 
 
2D representation of the chemical structure of Q27107323.
(+)-menthofuran

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

  1. ^ Anderson IB, Mullen WH, Meeker JE, Khojasteh-BakhtSC, Oishi S, Nelson SD, Blanc PD (April 1996). "Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature". Annals of Internal Medicine. 124 (8): 726–34. doi:10.7326/0003-4819-124-8-199604150-00004. PMID 8633832. S2CID 24375611.
  2. ^ Thomassen D, Knebel N, Slattery JT, McClanahan RH, Nelson SD (1992). "Reactive intermediates in the oxidation of menthofuran by cytochromes P-450". Chemical Research in Toxicology. 5 (1): 123–30. doi:10.1021/tx00025a021. PMID 1581528.
  3. ^ Mahmoud SS, Croteau RB (November 2003). "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. Bibcode:2003PNAS..10014481M. doi:10.1073/pnas.2436325100. PMC 283617. PMID 14623962.
  4. ^ 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.
  5. ^ 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. ^ a b 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.
  7. ^ 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.
  8. ^ Kramlinger VM, von Weymarn LB, Murphy SE (May 2012). "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. Bibcode:2012CBI...197...87K. doi:10.1016/j.cbi.2012.03.009. PMC 3362486. PMID 22486895.

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