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Nobiletin

Scientific Name(s): 2-(3,4)-dimethoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one
Common Name(s): Hexamethoxyflavone

Medically reviewed by Drugs.com. Last updated on Sep 2, 2019.

Clinical Overview

Use

Nobiletin has been shown to exhibit antioxidant, anti-inflammatory, antitumor/cancer, and antiangiogenic activity in vitro and in vivo. Animal and in vitro data also demonstrate nobiletin's potential ability to suppress bone loss, lower cholesterol and atherosclerosis, and improve hyperglycemia and insulin resistance.

Dosing

There are no specific dosing recommendations for nobiletin.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

There are no known adverse reactions associated with nobiletin.

Toxicology

No data.

Scientific Family

  • Flavone
  • Flavonoid

Botany

Nobiletin is found in the peel of fruits of the Citrus species (eg, king orange [Citrus nobilis], seville orange [Citrus aurantium]), and of the round kumquat (Fortunella japonica).NCBI 2017

History

Nobiletin was discovered by Kwong-Fong Tseng in the 1930s. Nobiletin was isolated from an oily matter from the Chinese drug chen-pi (made from the peel of C. nobilis, Lour [mandarin orange]) using a cold methanol extraction technique.Tseng 1938

Chemistry

Nobiletin is classified as a flavonoid based on its structure of 2-phenylchromen-4-one.NCBI 2017 It contains 6 methoxyl groups responsible for increased lipophilicity.Huang 2016, Li 2014 Nobiletin is a colorless solid with needle-like structures, and has a bitter taste.Kuroda 2016, Sasaki 2002

Uses and Pharmacology

Nobiletin has been shown to exhibit antioxidant, anti-inflammatory, antitumor/anticancer, and antiangiogenic activity in vitro and in vivo.NCBI 2017 Animal and in vitro data also demonstrate nobiletin's potential ability to suppress bone loss, lower cholesterol, reduce atherosclerosis, and improve hyperglycemia and insulin resistance.Lee 2010, Murakami 2007, Sasaki 2002, Whitman 2005

Anticancer activity

Animal and in vitro data

Nobiletin was shown to have a dose-dependent suppressive effect on the proliferation of A549 lung cancer cells.Luo 2008

Administration of a mixture of nobiletin and its major metabolites for 19 weeks to mice with colitis-associated colon carcinogenesis resulted in a decrease in cell cycle progression in the colon tissue, which was at least partially related to down-regulation of inducible nitric oxide synthase (iNOS).Wu 2017

Anti-inflammatory activity

Animal and in vitro data

The anti-inflammatory effects of nobiletin on human synovial fibroblasts and mouse macrophage J774A have been studied.Lin 2003 Nobiletin, at a concentration of 64 mcM, inhibited cyclooxygenase-2 (COX-2) production by 50%. A study of the effect of nobiletin on neuroinflammation found that nobiletin 50 mcM inhibited lipopolysaccharide (LPS)-induced iNOS expression by 71% compared with LPS alone.Cui 2010 Nobiletin was also shown to have a positive inhibitory effect on skin inflammation.Murakami 2000

Nobiletin 32 mcM was shown to decrease the production of proinflammatory cytokines in mouse J774A macrophages.Lin 2003

Nobiletin 50 mg/kg intravenously for 1 week prior to liver transplantation suppressed inflammatory response in rats, with less hepatocyte swelling and inflammatory cell infiltration and decreased ALT, AST, and lactate dehydrogenase compared with a group receiving saline only.Wu 2017

Antiobesity activity

Animal data

Nobiletin 17 mg/kg/day for 16 weeks improved glucose tolerance, insulin resistance, and total cholesterol levels in mice fed a high-fat diet, but did not affect food intake, body weight, or adiposity.Kim 2017 In a 5-week study of mice administered nobiletin 100 mg/kg/day, there was a decrease in body weight and fat mass without a reduction in food intake.Lee 2010

Bone loss

Animal data

In a study evaluating the effects of nobiletin on bone loss and arthritis in DBA/1J mice, suppression of reductions of whole bone mineral density comparable to that with 17beta-estradiol was observed, suggesting a role in prevention or treatment of osteoclastogenesis-related disorders, including osteoporosis.Murakami 2007

Cardiovascular activity

Animal data

In rats with streptozotocin-induced diabetes, 4 weeks of nobiletin 10 or 25 mg/kg orally daily resulted in improved mean arterial pressure, heart rate, and left ventricular end diastolic pressure. The 25 mg/kg dose also improved maximal left ventricular systolic pressure.Parkar 2016

CNS effects

Animal data

Nobiletin has been shown to have antioxidant and antidegenerative effects. The effects of nobiletin on cholinergic neurodegeneration in mice have been studied. In one study, intraperitoneal administration of 50 mg/kg/day for 11 days resulted in improvement in impaired memory.Nakajima 2007

When nobiletin was administered to rats for 9 days prior to the induction of brain ischemia, an increase in the neuroprotective effects of propofol was observed, with a decrease in the infarct area, apoptotic cell counts, and brain edema.Zheng 2017 In a study of rats with 1-methyl-4-phenylpyridinium (MPP)–induced Parkinson disease, intraperitoneal injections of nobiletin at doses of 1, 10, and 20 mg/kg for 7 days resulted in variable effects. A dose of 10 mg/kg prevented MPP-induced neuronal death compared with controls (P<0.01); however, the 1 and 20 mg/kg dosages did not result in significant differences.Jeong 2015

Nobiletin may have antidepressant activity, as it has a similar mechanism as the antidepressant minaprine, which has demonstrated effects in the hippocampus of mice.Nakajima 2007

Dosing

There are no specific dosing recommendations for nobiletin.

Interactions

No studies have been conducted to determine possible interactions of nobiletin with other drugs or compounds. Nobiletin suppresses platelet activity, Vaiyapuri 2015 and therefore may increase the bleeding risk of known antiplatelet or antithrombotic agents. Nobiletin is metabolized via cytochrome P450.

Adverse Reactions

There are no known adverse reactions associated with nobiletin.

Toxicology

Safety data sheets state that the lowest dose of nobiletin that caused a toxic effect in a mouse model was 25 mg/kg of body weight if administered intraperitoneally and 70 mg/kg of body weight if administered orally.Cayman 2017

References

Safety Data Sheet: Nobiletin. Cayman Chemical website. https://www.caymanchem.com/msdss/15421m.pdf. Accessed May 2, 2017.
Cui Y, Wu J, Jung SC, et al. Anti-neuroinflammatory activity of nobiletin on suppression of microglial activation. Biol Pharm Bull. 2010;33(11):1814-1821.21048305
English J. New dietary supplement shows dramatic effects in lowering cholesterol, LDL, and triglycerides. Nutrition Review website. https://nutritionreview.org/2013/04/dietary-supplement-shows-dramatic-effects-lowering-cholesterol-ldl-triglycerides/. Published April 26, 2013. Accessed May 7, 2017.
Huang H, Li L, Shi W, et al. The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. Evid Based Complement Alternat Med. 2016;2016:2918796.27761146
Jeong KH, Jeon MT, Kim HD, et al. Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease. J Med Food. 2015;18(4):409-414.25325362
Kim YJ, Choi MS, Woo JT, Jeong MJ, Kim SR, Jung UJ. Long-term dietary supplementation with low-dose nobiletin ameliorates hepatic steatosis, insulin resistance, and inflammation without altering fat mass in diet-induced obesity [published online ahead of print January 24, 2017]. Mol Nutr Food Res.2811677910.1002/mnfr.201600889
Kuroda Y, Ikeda R, Yamazaki T, et al. Activation of human bitter taste receptors by polymethoxylated flavonoids. Biosci Biotechnol Biochem. 2016;80(10):2014-2017.27379685
Lee YS, Cha BY, Saito K, et al. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem Pharmacol. 2010;79(11):1674-1683.20144590
Li S, Wang H, Guo L, Zhao H, Ho CT. Chemistry and bioactivity of nobiletin and its metabolites. J Funct Food. 2014:2-10.10.1016/j.jff.2013.12.011
Lin N, Sato T, Takayama Y, et al. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol. 2003;65(12):2065-2071.12787887
Luo G, Guan X, Zhou L. Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biol Ther. 2008;7(6):966-973.18379194
Ma W, Feng S, Yao X, Yuan Z, Liu L, Xie Y. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells. Sci Rep. 2015;5:18789.26689156
Murakami A, Nakamura Y, Torikai K, et al. Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res. 2000;60(18):5059-5066.11016629
Murakami A, Song M, Katsumata S, Uehara M, Suzuki K, Ohigashi H. Citrus nobiletin suppresses bone loss in ovariectomized ddY mice and collagen-induced arthritis in DBA/1J mice: possible involvement of receptor activator of NF-kappaB ligant (RANKL)-induced osteoclastogenesis regulation. Biofactors. 2007;30(3):179-192.18525112
Nakajima A, Yamakuni T, Haraguchi M, et al. Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci. 2007;105(1):122-126.17895593
National Center for Biotechnology Information. Nobiletin. PubChem Compound Database; CID=72344. https://pubchem.ncbi.nlm.nih.gov/compound/72344. Accessed May 4, 2017.
Parkar NA, Bhatt LK, Addepalli V. Efficacy of nobiletin, a citrus flavonoid, in the treatment of the cardiovascular dysfunction of diabetes in rats. Food Funct. 2016;7(7):3121-3129.27279123
Sasaki K, Yoshizaki F. Nobiletin as a tyrosinase inhibitor from the peel of Citrus fruit. Biol Pharm Bull. 2002;25(6):806-808.12081153
Tseng KF. 190. Nobiletin. Part I. J Chem Soc(Resumed). 1938:1003-1004.
Vaiyapuri S, Roweth H, Ali MS, et al. Pharmacological actions of nobiletin in the modulation of platelet function. Br J Pharmacol. 2015;172(16):4133-4145.25988959
Whitman SC, Kurowska EM, Manthey JA, Daugherty A. Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis. 2005;178(1):25-32.15585197
Wu X, Song M, Gao Z, et al. Nobiletin and its colonic metabolites suppress colitis-associated colon carcinogenesis by down-regulating iNOS, inducing antioxidative enzymes and arresting cell cycle progression. J Nutr Biochem. 2017;42:17-25.28107678
Zheng Y, Bu J, Yu L, Chen J, Liu H. Nobiletin improves propofol-induced neuroprotection via regulating Akt/mTOR and TLR 4/NF-κB signaling in ischemic brain injury in rats. Biomed Pharmacother. 2017;91:494-503.28478273

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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