| Record Information |
|---|
| Version | 1.0 |
|---|
| Created at | 2006-08-12 19:51:01 UTC |
|---|
| Updated at | 2021-10-07 20:38:50 UTC |
|---|
| NP-MRD ID | NP0000635 |
|---|
| Secondary Accession Numbers | None |
|---|
| Natural Product Identification |
|---|
| Common Name | d-Limonene |
|---|
| Description | (+)-Limonene, also known as d-limonene, is a naturally occurring monoterpene which is the major component in orange oil. Currently, (+)-limonene is widely used as a flavour 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, (+)-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to (+)-limonene causes a significant incidence of renal tubular tumours exclusively in male rats. Although (+)-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of (+)-limonene may raise some concern regarding the safety of (+)-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of (+)-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 (+)-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 (+)-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 (+)-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 demonstrates that the tumorigenic activity of (+)-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of (+)-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 (+)-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation (PMID: 2024047 ). |
|---|
| Structure | InChI=1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,10H,1,5-7H2,2-3H3/t10-/m0/s1 |
|---|
| Synonyms | | Value | Source |
|---|
| (+)-(4R)-Limonene | ChEBI | | (+)-(R)-Limonene | ChEBI | | (+)-4-Isopropenyl-1-methylcyclohexene | ChEBI | | (4R)-1-Methyl-4-isopropenylcyclohex-1-ene | ChEBI | | (4R)-4-Isopropenyl-1-methylcyclohexene | ChEBI | | (R)-(+)-Limonene | ChEBI | | (R)-(+)-p-Mentha-1,8-diene | ChEBI | | (R)-1-Methyl-4-(1-methylethenyl)cyclohexene | ChEBI | | (R)-4-Isopropenyl-1-methyl-1-cyclohexene | ChEBI | | (R)-p-Mentha-1,8-diene | ChEBI | | 4BetaH-p-mentha-1,8-diene | ChEBI | | D-(+)-Limonene | ChEBI | | D-Limonen | ChEBI | | D-Limonene | ChEBI | | (4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohexene | Kegg | | AISA 5203-L (+)limonene | HMDB | | Dipentene | HMDB | | (-)-Limonene | HMDB | | 1-Methyl-4-(1-methylethenyl)cyclohexene | HMDB | | Limonene | HMDB | | Limonene, (+-)-isomer | HMDB | | (D)-Limonene | HMDB | | 4-Mentha-1,8-diene | HMDB | | Limonene, (R)-isomer | HMDB | | (+)-Dipentene | HMDB | | (+)-alpha-Limonene | HMDB | | (+)-p-Mentha-1,8-diene | HMDB | | (+)-Α-limonene | HMDB | | (4R)-(+)-Limonene | HMDB | | (4R)-1-Methyl-4-(1-methylethenyl)cyclohexene | HMDB | | (4R)-Limonene | HMDB | | (R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-ene | HMDB | | (R)-Limonene | HMDB | | 1-Methyl-4-prop-1-en-2-yl-cyclohexene | HMDB | | (+)-(R)-4-Isopropenyl-1-methylcyclohexene | HMDB | | D Limonene | HMDB | | 4 Mentha 1,8 diene | HMDB | | (R)-4-Isopropenyl-1-methylcyclohexene | HMDB | | (4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-ene | HMDB | | R-Limonene | HMDB | | p-Mentha-1,8-diene | HMDB | | (±)-dipentene | HMDB | | (±)-limonene | HMDB | | (±)-alpha-limonene | HMDB | | (±)-α-limonene | HMDB | | 1,8-p-Menthadiene | HMDB | | 1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-ene | HMDB | | 1-Methyl-4-isopropenyl-1-cyclohexene | HMDB | | 1-Methyl-4-isopropenylcyclohexene | HMDB | | 1-Methyl-p-isopropenyl-1-cyclohexene | HMDB | | 4-Isopropenyl-1-methyl-1-cyclohexene | HMDB | | 4-Isopropenyl-1-methylcyclohexene | HMDB | | DL-Limonene | HMDB | | Dipenten | HMDB | | Limonen | HMDB | | alpha-Limonene | HMDB | | Α-limonene | HMDB | | (+)-Limonene | HMDB, ChEBI |
|
|---|
| Chemical Formula | C10H16 |
|---|
| Average Mass | 136.2340 Da |
|---|
| Monoisotopic Mass | 136.12520 Da |
|---|
| IUPAC Name | (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene |
|---|
| Traditional Name | α-limonene |
|---|
| CAS Registry Number | 5989-54-8 |
|---|
| 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-/m0/s1 |
|---|
| InChI Key | XMGQYMWWDOXHJM-JTQLQIEISA-N |
|---|
| Experimental Spectra |
|---|
|
| | Spectrum Type | Description | Depositor Email | Depositor Organization | Depositor | Deposition Date | View |
|---|
| 2D NMR | [1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, CDCl3, experimental) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum |
| | Predicted Spectra |
|---|
|
| | Spectrum Type | Description | Depositor ID | Depositor Organization | Depositor | Deposition Date | View |
|---|
| 1D NMR | 13C NMR Spectrum (1D, 25 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 100 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 1000 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 252 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 50 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 200 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 75 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 300 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 101 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 400 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 126 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 500 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 600 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 151 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 700 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 176 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 201 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 800 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 1H NMR Spectrum (1D, 900 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum | | 1D NMR | 13C NMR Spectrum (1D, 226 MHz, D2O, predicted) | Wishart Lab | Wishart Lab | David Wishart | 2021-06-20 | View Spectrum |
| | Chemical Shift Submissions |
|---|
|
| Not Available | | Species |
|---|
| Species of Origin | |
|---|
| Chemical Taxonomy |
|---|
| Description | 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. |
|---|
| Kingdom | Organic compounds |
|---|
| Super Class | Lipids and lipid-like molecules |
|---|
| Class | Prenol lipids |
|---|
| Sub Class | Monoterpenoids |
|---|
| Direct Parent | Menthane monoterpenoids |
|---|
| Alternative Parents | |
|---|
| Substituents | - P-menthane monoterpenoid
- Monocyclic monoterpenoid
- Branched unsaturated hydrocarbon
- Cycloalkene
- Cyclic olefin
- Unsaturated aliphatic hydrocarbon
- Unsaturated hydrocarbon
- Olefin
- Hydrocarbon
- Aliphatic homomonocyclic compound
|
|---|
| Molecular Framework | Aliphatic homomonocyclic compounds |
|---|
| External Descriptors | |
|---|
| Physical Properties |
|---|
| State | Liquid |
|---|
| Experimental Properties | | Property | Value | Reference |
|---|
| Melting Point | -90 °C | Not Available | | Boiling Point | 175.00 to 177.00 °C. @ 760.00 mm Hg | The Good Scents Company Information System | | Water Solubility | 13.8 mg/L @ 25 °C (exp) | The Good Scents Company Information System | | LogP | 4.38 | Griffin, S., Wyllie, S. G., & Markham, J. (1999). Determination of octanol-water partition coefficient for terpenoids using reversed-phase high-performance liquid chromatography. Journal of Chromatography A, 864(2), 221-228. |
|
|---|
| Predicted Properties | |
|---|
| General References | - 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. [PubMed:10370194 ]
- 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. [PubMed:11472817 ]
- 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. [PubMed:12399762 ]
- 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. [PubMed:2310709 ]
- 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. [PubMed:16451823 ]
- 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. [PubMed:8932680 ]
- 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. [PubMed:7536240 ]
- 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. [PubMed:2024047 ]
|
|---|
