D-limonene

D-limonene

D-limonene

Common Names

  • R-limonene
  • orange peel oil
  • citrus peel oil
  • citrene

For Patients & Caregivers

Bottom Line: D-limonene has not been shown to treat or prevent cancer.

D-limonene is made from the peels of citrus fruits. Scientists are not exactly sure how it works, but it showed anticancer activity in laboratory studies. These studies suggest that D-limonene alters the signaling pathways within cancer cells in a way that stops cancer cells from multiplying and causes their death (this is called “apoptosis”). In animals, D-limonene slowed the growth of pancreatic, stomach, colon, skin, and liver cancers. It also slowed formation of tumors and their progression in animals exposed to cancer-causing substances. However, these anticancer effects have not been shown in humans.

  • To prevent and treat cancer
    Although test tube and animal studies show that D-limonene has anti-cancer activity, this effect was not found in early clinical trials.
  • To treat heartburn and gastroesophageal reflux
    There is limited evidence to support this use. More studies are needed.
  • Nausea
  • Vomiting
  • Diarrhea
  • Allergic skin rash
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For Healthcare Professionals

p-mentha-1,8-diene

Derived from the peels of citrus fruits, D-limonene is used by patients to prevent and treat cancer and has been promoted as a treatment for gastroesophageal reflux. Following oral administration, D-limonene is rapidly metabolized to limonene-1,2-diol, perillic acid, dihydroperillic acid, and uroterpenol (1)(2)(3).
In vitro and animal studies suggest that D-limonene has anti-inflammatory (13), bactericidal (19) and anticancer effects (14)(16)(17)(18). It was also shown to enhance the activity of docetaxel against prostate cancer cells (15).
An epidemiological study reported an inverse relationship between citrus peel consumption and squamous cell carcinoma (4), but an early clinical trial in breast cancer patients failed to support the observations (5)(6).
Further research is necessary to determine if D-limonene has a role in the prevention or treatment of cancer.

  • Cancer prevention
  • Cancer treatment
  • Heartburn and GERD (gastroesophageal reflux)

D-Limonene and its metabolites, perillic acid, dihydroperillic acid, uroterpenol, and limonene1,2-diol, may inhibit tumor growth via inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway (9)(10). D-Limonene metabolites also cause G1 cell cycle arrest, inhibit post-translational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes (6).
D-limonene induces apoptosis via the mitochondrial death pathway and suppression of the PI3K/Akt pathway in human colon cancer cells (16).
Animal studies show activity of D-limonene against pancreatic, stomach, colon, skin, and liver cancers (5)(17). Data also indicate that D-limonene slows the promotion/progression stage of carcinogen-induced tumors in rats (11)(12).
The chemopreventive activity of D-limonene may be via inhibition of inflammation, oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state in a mouse model of skin tumorigenesis (18).

Following oral administration, D-limonene is absorbed rapidly and metabolized to perillic acid (PA), dihydroperillic acid (DPA), limonene1,2-diol, and uroterpenol. D-Limonene metabolites distribute throughout the body to all sites, including adipose tissue, and are eliminated as glucuronide metabolites in the urine (1)(2)(3).

  • Nausea, vomiting, diarrhea (3)
  • Case Reports: Contact Dermatitis (7) and asthma (8) have been reported.

  1. Crowell PL, et al. Human metabolism of the experimental cancer therapeutic agent d-limonene. Cancer Chemother Pharmacol 1994;35:31-7.

  2. Hardcastle IR, et al. Inhibition of protein prenylation by metabolites of limonene. Biochem Pharmacol 1999;57:801-9.

  3. Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Chemother Pharmacol 1998;42:111-7.

  4. Hakim IA, Harris RB, Ritenbaugh C. Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin. Nutr Cancer. 2000;37(2):161-168.

  5. Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev 1998;3:448-57.

  6. Reddy BS, et al. Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 1997;57:420-5.

  7. Topham EJ, Wakelin SH. D-Limonene contact dermatitis from hand cleansers. Contact Dermatitis. 2003 Aug;49(2):108-9.

  8. Guarneri F, Barbuzza O, Vaccaro M, et al. Allergic contact dermatitis and asthma caused by limonene in a labourer handling citrus fruits. Contact Dermatitis. May 2008;58(5):315-316.

  9. Chidambara Murthy KN, Jayaprakasha GK, Patil BS. D-limonene rich volatile oil from blood oranges inhibits angiogenesis, metastasis and cell death in human colon cancer cells.Life Sci. 2012 Oct 5;91(11-12):429-39.

  10. Chaudhary SC, Siddiqui MS, Athar M, Alam MS. D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis.Hum Exp Toxicol. 2012 Aug;31(8):798-811.

  11. Espina L, Gelaw TK, de Lamo-Castellví S, Pagán R, García-Gonzalo D. Mechanism of bacterial inactivation by (+)-limonene and its potential use in food preservation combined processes. PLoS One. 2013;8(2):e56769.

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