Menthofuran

Last updated
Menthofuran
Menthofuran.svg
Names
IUPAC name
3,6-Dimethyl-4,5,6,7-tetrahydro-1-benzofuran
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.007.087 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
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]

Contents

Biosynthesis

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

Menthofuran synthase converts pulegone to menthofuran (+)-menthofuran synthase reaction.PNG
Menthofuran synthase converts pulegone to 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. [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]

Related Research Articles

<i>Mentha pulegium</i> Species of plant

Mentha pulegium, commonly (European) pennyroyal, or pennyrile, also called mosquito plant and pudding grass, is a species of flowering plant in the mint family, Lamiaceae, native to Europe, North Africa, and the Middle East. Crushed pennyroyal leaves emit a very strong fragrance similar to spearmint. Pennyroyal is a traditional folk remedy, emmenagogue, abortifacient, and culinary herb, but is toxic to the liver and has caused some deaths. European pennyroyal is related to an American species, Hedeoma pulegioides. Though they differ in genera, they share similar chemical properties.

Detoxification or detoxication is the physiological or medicinal removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver. Additionally, it can refer to the period of drug withdrawal during which an organism returns to homeostasis after long-term use of an addictive substance. In medicine, detoxification can be achieved by decontamination of poison ingestion and the use of antidotes as well as techniques such as dialysis and chelation therapy.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown, steroid hormone synthesis, drug metabolism, and the biosynthesis of defensive compounds, fatty acids, and hormones. CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. In almost all of the transformations that they catalyze, P450's effect hydroxylation.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<span class="mw-page-title-main">CYP2E1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzymatic metabolism in the organisms, as well as by abiotic chemical reactions. While the parent drug are usually less active, both the parent drug and its metabolite can be chemically active and cause toxicity, leading to mutagenesis, teratogenesis, and carcinogenesis. Different classes of enzymes, such as P450-monooxygenases, epoxide hydrolase, or acetyltransferases can catalyze the process in the cell, mostly in the liver.

<span class="mw-page-title-main">Quercetin</span> Chemical compound

Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor and is used as an ingredient in dietary supplements, beverages, and foods.

<span class="mw-page-title-main">Tienilic acid</span> Chemical compound

Tienilic acid or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.

Toluene toxicity refers to the harmful effects caused by toluene on the body.

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

<span class="mw-page-title-main">Hexobarbital</span> Chemical compound

Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. Modern barbiturates have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.

<span class="mw-page-title-main">NAPQI</span> Toxic byproduct of acetaminophen

NAPQI, also known as NAPBQI or N-acetyl-p-benzoquinone imine, is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.

<span class="mw-page-title-main">CYP2B6</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.

<span class="mw-page-title-main">Flunoxaprofen</span> Chemical compound

Flunoxaprofen, also known as Priaxim, is a chiral nonsteroidal anti-inflammatory drug (NSAID). It is closely related to naproxen, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms of osteoarthritis and rheumatoid arthritis. The clinical use of flunoxaprofen has ceased due to concerns of potential hepatotoxicity.

Benoxaprofen, also known as Benoxaphen, is a chemical compound with the formula C16H12ClNO3. It is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, and was marketed under the brand name Opren in the United Kingdom and Europe by Eli Lilly and Company (commonly referred to as Lilly), and as Oraflex in the United States of America (USA). Lilly suspended sales of Oraflex in 1982 after reports from the British government and the United States Food and Drug Administration (US FDA) of adverse effects and deaths linked to the drug.

<span class="mw-page-title-main">CYP3A5</span> Enzyme involved in drug metabolism

Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.

Cunninghamella elegans is a species of fungus in the genus Cunninghamella found in soil.

<span class="mw-page-title-main">4-Ipomeanol</span> Chemical compound

4-Ipomeanol (4-IPO) is a pulmonary pre-toxin isolated from sweet potatoes infected with the fungus Fusarium solani. One of the 4-IPO metabolites is toxic to the lungs, liver and kidney in humans and animals. This metabolite can covalently bind to proteins, thereby interfering with normal cell processes.

<span class="mw-page-title-main">Nicotyrine</span> Chemical compound

Nicotryine is lesser known and minor tobacco alkaloid. It inhibits metabolism of nicotine through CYP2A6 enzyme inhibition. It also inhibits CYP2A13 which might play role in nicotine metabolism. Nicotyrine is formed by gradual oxidation of nicotine in e-liquids and causes delayed nicotine clearance and attenuated withdrawal symptoms.

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. 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 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
  4. 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.
  5. 1 2 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. PMID   2891472.
  6. 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. PMID   1686249.
  7. 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.