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Record Information
Version3.6
Creation Date2006-08-12 19:51:01 UTC
Update Date2016-02-11 01:06:13 UTC
HMDB IDHMDB03375
Secondary Accession NumbersNone
Metabolite Identification
Common NameD-Limonene
DescriptionThe monoterpene d-limonene is a naturally occurring chemical which is the major component in oil of orange. Currently, d-limonene is widely used as a flavor and fragrance and is listed to be generally recognized as safe in food by the Food and Drug Administration (21 CFR 182.60 in the Code of Federal Regulations, U.S.A.). Recently, however, d-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to d-limonene causes a significant incidence of renal tubular tumors exclusively in male rats. Although d-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of d-limonene may raise some concern regarding the safety of d-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of d-limonene results from the accumulation of a protein, alpha 2u-globulin, in male rat kidney proximal tubule lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with alpha 2u-globulin. However, none of these proteins, including the mouse equivalent of alpha 2u-globulin, can produce this toxicity, indicating a unique specificity for alpha 2u-globulin. With chronic exposure to d-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensatory cell proliferation. Both d-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in vitro mutagenicity screens. Therefore, the toxicity-related renal cell proliferation is believed to be integrally involved in the carcinogenicity of d-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The scientific data base demonstrates that the tumorigenic activity of d-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of d-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that alpha 2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both d-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation. (PMID: 2024047 ).
Structure
Thumb
Synonyms
ValueSource
(-)-(S)-LimoneneChEBI
(-)-(4S)-LimoneneChEBI
(-)-LimoneneChEBI
(4S)-1-Methyl-4-isopropenylcyclohex-1-eneChEBI
(4S)-4-Isopropenyl-1-methylcyclohexeneChEBI
(S)-(-)-P-Mentha-1,8-dieneChEBI
(S)-1-Methyl-4-(1-methylethenyl)cyclohexeneChEBI
(S)-P-Mentha-1,8-dieneChEBI
4AlphaH-P-mentha-1,8-dieneChEBI
L-LimonenChEBI
L-LimoneneChEBI
4-Isopropenyl-1-methyl-1-cyclohexeneHMDB
LimoneneHMDB
Chemical FormulaC10H16
Average Molecular Weight136.234
Monoisotopic Molecular Weight136.125200512
IUPAC Name(4S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene
Traditional Name(-)-limonene
CAS Registry Number5989-54-8
SMILES
CC(=C)[C@H]1CCC(C)=CC1
InChI Identifier
InChI=1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,10H,1,5-7H2,2-3H3/t10-/m1/s1
InChI KeyInChIKey=XMGQYMWWDOXHJM-SNVBAGLBSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as menthane monoterpenoids. These are monoterpenoids with a structure based on the o-, m-, or p-menthane backbone. P-menthane consists of the cyclohexane ring with a methyl group and a (2-methyl)-propyl group at the 1 and 4 ring position, respectively. The o- and m- menthanes are much rarer, and presumably arise by alkyl migration of p-menthanes.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassMonoterpenoids
Direct ParentMenthane monoterpenoids
Alternative Parents
Substituents
  • Menthane monoterpenoid
  • Monocyclic monoterpenoid
  • Cycloalkene
  • Cyclic olefin
  • Olefin
  • Hydrocarbon
  • Aliphatic homomonocyclic compound
Molecular FrameworkAliphatic homomonocyclic compounds
External Descriptors
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
  • Food
Biofunction
  • Cell signaling
  • Component of Monoterpenoid biosynthesis
  • Fuel and energy storage
  • Fuel or energy source
  • Membrane integrity/stability
Application
  • Nutrients
  • Stabilizers
  • Surfactants and Emulsifiers
Cellular locations
  • Cytoplasm
  • Extracellular
  • Membrane (predicted from logP)
Physical Properties
StateLiquid
Experimental Properties
PropertyValueReference
Melting Point-90 °CNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogP4.38GRIFFIN,S ET AL. (1999)
Predicted Properties
PropertyValueSource
Water Solubility0.46 mg/mLALOGPS
logP4.5ALOGPS
logP3.22ChemAxon
logS-2.5ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity46.48 m3·mol-1ChemAxon
Polarizability17.23 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-001c-8900000000-dfd6c14e6a4e49bfc6dcView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-002f-9000000000-06c43b864c090aaae8aeView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-01t9-9000000000-e5ee54500bc5feda4631View in MoNA
MSMass Spectrum (Electron Ionization)splash10-014l-9100000000-7e8881e736cecb723a2bView in MoNA
1D NMR1H NMR SpectrumNot Available
2D NMR[1H,13C] 2D NMR SpectrumNot Available
Biological Properties
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane (predicted from logP)
Biofluid Locations
  • Blood
  • Feces
  • Urine
Tissue Location
  • Skin
  • Stratum Corneum
PathwaysNot Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.19 (0.02 - 2.40) uMAdult (>18 years old)BothNormal details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
details
FecesDetected but not QuantifiedNot ApplicableNewborn (0-30 days old)Both
Normal
details
UrineDetected but not QuantifiedNot ApplicableAdult (>18 years old)BothNormal details
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Nonalcoholic fatty liver disease (NAFLD)
details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Campylobacter jejuni infection
details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Clostridium difficile infection
details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Ulcerative Colitis
details
UrineDetected but not QuantifiedNot ApplicableAdult (>18 years old)BothBreast cancer details
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB013861
KNApSAcK IDC00000803
Chemspider ID388386
KEGG Compound IDC00521
BioCyc ID-R-LIMONENE
BiGG ID47361
Wikipedia LinkLimonene
NuGOwiki LinkHMDB03375
Metagene LinkHMDB03375
METLIN ID6911
PubChem Compound439250
PDB IDNot Available
ChEBI ID15383
References
Synthesis Referencev. Braun, Julius; Lemke, Georg. Preparation of pure d- and l-limonene. Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1923), 56B 1562-3.
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Bhatia KS, Singh J: Effect of linolenic acid/ethanol or limonene/ethanol and iontophoresis on the in vitro percutaneous absorption of LHRH and ultrastructure of human epidermis. Int J Pharm. 1999 Apr 15;180(2):235-50. [10370194 ]
  2. Cal K, Janicki S, Sznitowska M: In vitro studies on penetration of terpenes from matrix-type transdermal systems through human skin. Int J Pharm. 2001 Aug 14;224(1-2):81-8. [11472817 ]
  3. Matura M, Goossens A, Bordalo O, Garcia-Bravo B, Magnusson K, Wrangsjo K, Karlberg AT: Oxidized citrus oil (R-limonene): a frequent skin sensitizer in Europe. J Am Acad Dermatol. 2002 Nov;47(5):709-14. [12399762 ]
  4. Falk A, Gullstrand E, Lof A, Wigaeus-Hjelm E: Liquid/air partition coefficients of four terpenes. Br J Ind Med. 1990 Jan;47(1):62-4. [2310709 ]
  5. Lim PF, Liu XY, Kang L, Ho PC, Chan YW, Chan SY: Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol. Int J Pharm. 2006 Mar 27;311(1-2):157-64. Epub 2006 Jan 31. [16451823 ]
  6. Yamane MA, Williams AC, Barry BW: Terpene penetration enhancers in propylene glycol/water co-solvent systems: effectiveness and mechanism of action. J Pharm Pharmacol. 1995 Dec;47(12A):978-89. [8932680 ]
  7. Cornwell PA, Barry BW, Stoddart CP, Bouwstra JA: Wide-angle X-ray diffraction of human stratum corneum: effects of hydration and terpene enhancer treatment. J Pharm Pharmacol. 1994 Dec;46(12):938-50. [7536240 ]
  8. Flamm WG, Lehman-McKeeman LD: The human relevance of the renal tumor-inducing potential of d-limonene in male rats: implications for risk assessment. Regul Toxicol Pharmacol. 1991 Feb;13(1):70-86. [2024047 ]

Enzymes

General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular weight:
55627.365
Reactions
D-Limonene + NADPH + Oxygen → (-)-trans-Carveol + NADP + Waterdetails
D-Limonene + NADPH + Oxygen → (S)-p-Mentha-1,8-dien-7-ol + NADP + Waterdetails
General function:
Involved in monooxygenase activity
Specific function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular weight:
55944.565
Reactions
D-Limonene + NADPH + Oxygen → (-)-trans-Carveol + NADP + Waterdetails
D-Limonene + NADPH + Oxygen → (S)-p-Mentha-1,8-dien-7-ol + NADP + Waterdetails