Menthofuran
{{Chembox
| ImageFile = Menthofuran.svg
| ImageSize = 200px
| IUPACName = 3,6-Dimethyl-4,5,6,7-tetrahydro-1-benzofuran
| OtherNames =
|Section1={{Chembox Identifiers
| CASNo = 494-90-6
| CASNo_Ref = {{cascite|correct|}}
| CASNo1 = 17957-94-7
| CASNo1_Comment = (R)
| CASNo1_Ref = {{cascite|correct|}}
| CASNo2 = 80183-38-6
| CASNo2_Comment = (S)
| CASNo2_Ref = {{cascite|correct|}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = LK024V9U3C
| UNII1_Ref = {{fdacite|correct|FDA}}
| UNII1 = 9N0IS8189W
| UNII1_Comment = (R)
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = OS9602CGD2
| UNII2_Comment = (S)
| PubChem = 329983
| ChemSpiderID = 292309
| ChEBI = 50542
| SMILES = o1c2c(c(c1)C)CCC(C2)C
| InChI = 1/C10H14O/c1-7-3-4-9-8(2)6-11-10(9)5-7/h6-7H,3-5H2,1-2H3
| InChIKey = YGWKXXYGDYYFJU-UHFFFAOYAW
| StdInChI = 1S/C10H14O/c1-7-3-4-9-8(2)6-11-10(9)5-7/h6-7H,3-5H2,1-2H3
| StdInChIKey = YGWKXXYGDYYFJU-UHFFFAOYSA-N
}}
|Section2={{Chembox Properties
| C=10 | H=14 | O=1
| Appearance =
| Density =
| MeltingPt =
| BoilingPt = 208
| Solubility =
}}
|Section3={{Chembox Hazards
| MainHazards =
| FlashPt = 86
| AutoignitionPt =
}}
}}
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.{{cite journal | vauthors = Anderson IB, Mullen WH, Meeker JE, Khojasteh-BakhtSC, Oishi S, Nelson SD, Blanc PD | title = Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature | journal = Annals of Internal Medicine | volume = 124 | issue = 8 | pages = 726–34 | date = April 1996 | pmid = 8633832 | doi = 10.7326/0003-4819-124-8-199604150-00004| s2cid = 24375611 }} After ingestion of menthofuran, it is metabolically activated to chemically reactive intermediates that are hepatotoxic.{{cite journal | vauthors = Thomassen D, Knebel N, Slattery JT, McClanahan RH, Nelson SD | title = Reactive intermediates in the oxidation of menthofuran by cytochromes P-450 | journal = Chemical Research in Toxicology | volume = 5 | issue = 1 | pages = 123–30 | date = 1992 | pmid = 1581528 | doi = 10.1021/tx00025a021}}
Biosynthesis
Menthofuran is produced biosynthetically from pulegone by the enzyme menthofuran synthase.
:File:(+)-menthofuran synthase reaction.PNG{{clear left}}
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.{{cite journal | author = Mariko Aso| title = Furannulation strategy. An efficient synthesis of fused 3-methylfurans| journal = Heterocycles| volume = 31 | issue = 6| pages = 1003–6| year = 1990| last2 = Sakamoto| first2 = Mizue| last3 = Urakawa| first3 = Narumi| last4 = Kanematsu| first4 = Ken| doi=10.3987/com-90-5392| doi-access = free}}
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.{{cite journal|last1=Khojasteh-Bakh|first1=S. C.|last2=Koenigs|first2=L. L.|last3=Peter|first3=R. M.|last4=Trager|first4=W. F.|last5=Nelson|first5=S. D.|title=(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6|journal=Drug Metabolism and Disposition|date=July 1998|volume=26|issue=7|pages=701–704|pmid=9660853}}{{cite journal|last1=Gordon|first1=W. P.|last2=Huitric|first2=A. C.|last3=Seth|first3=C. L.|last4=McClanahan|first4=R. H.|last5=Nelson|first5=S. D.|title=The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofuran|journal=Drug Metabolism and Disposition|date=February 26, 1989|volume=15|issue=5|pages=589–594|doi=10.1016/S0090-9556(25)06790-X |pmid=2891472}}{{cite journal|last1=Thomassen|first1=D.|last2=Pearson|first2=P. G.|last3=Slattery|first3=J. T.|last4=Nelson|first4=S. D.|title=Partial characterization of biliary metabolites of pulegone by tandem mass spectrometry. Detection of glucuronide, glutathione, and glutathionyl glucuronide conjugates.|journal=Drug Metabolism and Disposition|date=January 17, 1991|volume=19|issue=5|pages=997–104|doi=10.1016/S0090-9556(25)08983-4 |pmid=1686249}}{{cite journal |vauthors=Kramlinger VM, von Weymarn LB, Murphy SE |title=Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, β-nicotyrine and menthol |journal=Chemico-Biological Interactions |volume=197 |issue=2–3 |pages=87–92 |date=May 2012 |pmid=22486895 |pmc=3362486 |doi=10.1016/j.cbi.2012.03.009 |bibcode=2012CBI...197...87K |url= |issn=}}
Menthofuran may deplete glutathione levels, leaving hepatocytes vulnerable to free radical damage.