Diosmetin

Diosmetin at a Glance

Diosmetin is a naturally occurring methylated flavone — chemically 3’,5,7-trihydroxy-4’-methoxyflavone, which is simply luteolin with a methyl group added at the 4’ position of the B ring ^{6Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}. That single methylation is the whole story of this molecule: it makes diosmetin the aglycone of diosmin, the citrus flavone glycoside used as a venotonic drug, and it sits one demethylation step away from luteolin in both directions of metabolism ^{2,3Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →}.

Most of what looks like “diosmetin evidence” is really evidence for diosmin, the whole drug. After diosmin is swallowed, gut bacteria cleave off its rutinose sugar to release diosmetin, which is then absorbed and conjugated — so diosmin’s established clinical use in chronic venous insufficiency and haemorrhoids is, mechanistically, delivered through diosmetin, but the trials were run on the glycoside, not the isolated aglycone ^{2,11Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 11Chen X et al. · 2019AnimalProfiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSnView study →}.

The free molecule’s own pharmacology — anti-inflammatory, antioxidant/cytoprotective, anticancer and antidiabetic signals — is almost entirely preclinical (cell and rodent work on the isolate) ^{1Reference 1Patel K et al. · 2013ReviewA review on pharmacological and analytical aspects of diosmetin: a concise reportView study →}. Dietary exposure to diosmetin from citrus and herbs is low and its toxicity is correspondingly low, with the main theoretical cautions being its weak phytoestrogen activity and its inhibition of drug-metabolising CYP1 enzymes ^{3,6Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}.

Diosmetin, Diosmin & Luteolin

The point is a three-molecule relationship that a reader will otherwise conflate. All three differ only in what decorates the flavone core:

• Diosmin — diosmetin 7-O-rutinoside, the glycoside. This is the actual drug (often combined with hesperidin as micronised purified flavonoid fraction) prescribed for venous disease. It is poorly absorbed intact.
• Diosmetin — the aglycone. Released from diosmin by gut-bacterial hydrolysis of the sugar, it is the form that is actually absorbed into the circulation and then glucuronidated/sulfated ^{2,11Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 11Chen X et al. · 2019AnimalProfiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSnView study →}.
• Luteolin — diosmetin’s 4’-demethylated relative. Human CYP1 enzymes (CYP1A1, CYP1B1 and hepatic CYP1A2) can strip the 4’-methyl off diosmetin, converting it back to luteolin ^{3,6Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}.

So diosmetin is metabolically downstream of diosmin and upstream of luteolin — swallow diosmin, and the body walks it down this chain.

The methyl position also separates diosmetin from its batch-mate chrysoeriol, which is luteolin’s 3’-methyl ether (the methyl on the other B-ring hydroxyl). Diosmetin (4’-OCH₃) and chrysoeriol (3’-OCH₃) are positional isomers with the same formula but different enzyme-binding behaviour — the 4’-methoxy/5,7-dihydroxy arrangement is specifically what makes diosmetin a potent CYP1 inhibitor ^{5Reference 5Androutsopoulos VP et al. · 2011Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoidsView study →}. A third relative, acacetin, is apigenin’s 4’-methyl ether — the same 4’-methylation applied to a flavone lacking the 3’-hydroxyl ^{5,6Reference 5Androutsopoulos VP et al. · 2011Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoidsView study →Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}.

What It's Used For

Diosmetin’s evidence divides cleanly into two piles: a real human-drug record that belongs to diosmin (delivered via diosmetin), and a broad but preclinical isolate signal. The load-bearing discipline is not to let the first pile lend unearned weight to the second.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. The top row scores partly on diosmin (the drug diosmetin is derived from), not the isolated aglycone — read the per-row basis.

01Venotonic / Microcirculation (as diosmin)Promising52%Established clinical use of the glycoside diosmin; diosmetin is its absorbed aglycone ^{2,11Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 11Chen X et al. · 2019AnimalProfiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSnView study →}

02Anti-InflammatoryShaky38%Rodent colitis & atopic-dermatitis isolate models; NF-κB/MAPK/Sirt1 ^{7,8Reference 7Li HL et al. · 2022Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axisView study →Reference 8Lee DH et al. · 2020Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis modelView study →}

03Anticancer / CYP1 BioactivationShaky34%In-vitro isolate; CYP1B1 inhibition + demethylation to luteolin ^{3,4,5,6Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →Reference 4Androutsopoulos VP et al. · 2009Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activationView study →Reference 5Androutsopoulos VP et al. · 2011Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoidsView study →Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}

04Antioxidant / CytoprotectionShaky30%Rodent/cell isolate; Nrf2–HO-1, AMPK-autophagy ^{7,9,10Reference 7Li HL et al. · 2022Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axisView study →Reference 9He WS et al. · 2022Diosmetin inhibits apoptosis and activates AMPK-induced autophagy in myocardial damage under hypoxia environmentView study →Reference 10Si Q et al. · 2020Diosmetin alleviates hypoxia-induced myocardial apoptosis by inducing autophagy through AMPK activationView study →}

05Antidiabetic / MetabolicShaky22%Largely diosmin-level + in-silico enzyme-binding ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}

Mechanisms

The load-bearing rows are the CYP1 pair: diosmetin inhibits the carcinogen-activating enzymes yet is converted by them to luteolin — the same reaction that links this whole methylated-flavone family ^{3,5,6Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →Reference 5Androutsopoulos VP et al. · 2011Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoidsView study →Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}.

Pharmacokinetics

Diosmetin’s PK is best understood as the downstream half of diosmin’s. Swallowed diosmin is barely absorbed intact; gut microbiota hydrolyse it to diosmetin, and it is this aglycone that enters the circulation before being esterified into glucuronide (and sulfate) conjugates excreted in the urine ^{2,11Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 11Chen X et al. · 2019AnimalProfiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSnView study →}. Diosmetin itself is extensively phase-II metabolised — a rat metabolite-profiling study identified dozens of methylation, demethylation, glucuronidation, diglucuronidation and sulfation products and, tellingly, could not detect free diosmetin in urine, plasma or faeces, indicating it is rapidly transformed in vivo ^{11Reference 11Chen X et al. · 2019AnimalProfiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSnView study →}. Like most flavone aglycones it has low aqueous solubility and modest oral bioavailability, which is why the diosmin drug is micronised to improve absorption ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}. Robust human ADME for the isolate — Cmax, half-life, absolute bioavailability — is not well characterised; the human data that exist are for the diosmin drug, within which diosmetin is the transient aglycone ^{2,11Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 11Chen X et al. · 2019AnimalProfiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSnView study →}.

Clinical Trials

Human clinical evidence exists for diosmin, not for isolated diosmetin. Diosmin (largely as the diosmin/hesperidin combination) has been evaluated in venous insufficiency and haemorrhoidal disease with a favourable safety record ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}; there are no controlled efficacy trials of the free aglycone as a stand-alone agent.

Last checked: July 2026.

Isolate vs. Plant Studies

Diosmetin’s evidence base is unusual because the “vehicle” is not a plant but a purified glycoside drug. The strongest human-relevant data come from diosmin — a single, well-defined flavonoid preparation — of which diosmetin is the absorbed aglycone ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}. That is cleaner than a botanical extract, but it is still not the free aglycone tested on its own: no trial has dosed isolated diosmetin and measured a clinical outcome. The mechanistic and efficacy work that does use pure diosmetin — colitis, atopic dermatitis, cardiomyocyte hypoxia, breast-cancer cells — is rodent and in-vitro ^{3,4,7,8,9Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →Reference 4Androutsopoulos VP et al. · 2009Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activationView study →Reference 7Li HL et al. · 2022Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axisView study →Reference 8Lee DH et al. · 2020Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis modelView study →Reference 9He WS et al. · 2022Diosmetin inhibits apoptosis and activates AMPK-induced autophagy in myocardial damage under hypoxia environmentView study →}. As a constituent of whole herbs (rosemary, hyssop, marshmallow, buchu), diosmetin is a minor flavone among many and is not individually credited with those herbs’ effects ^{1Reference 1Patel K et al. · 2013ReviewA review on pharmacological and analytical aspects of diosmetin: a concise reportView study →}. The correct framing: a real drug record for the glycoside, a broad preclinical signal for the isolate, and no direct human data for free diosmetin.

Prevalence in Nature

Diosmetin occurs across several plant families but almost always bound as glycosides rather than free — most importantly as diosmin (diosmetin 7-O-rutinoside), and as C- and O-glycosides. It is classically a citrus flavone, present in the fruit, peel and juice of Citrus species; in the Sardinian citrus ecotype pompia, for instance, diosmetin 6,8-C-diglucoside was measured at ~54.5 mg/L of juice ^{13Reference 13Posadino AM et al. · 2024ReviewCitrus limon var. pompia Camarda var. nova: A Comprehensive Review of Its Botanical Characteristics, Traditional Uses, Phytochemical Profile, and Potential Health BenefitsView study →}. It also appears in aromatic Lamiaceae — rosemary and hyssop (where diosmin runs to ~1.7% of the dry shoot) — and in buchu (Agathosma), marshmallow (Althaea officinalis, as diosmetin glucosides linked to antibacterial activity) ^{15Reference 15Mehreen A et al. · 2016Phytochemical, Antimicrobial, and Toxicological Evaluation of Traditional Herbs Used to Treat Sore ThroatView study →}, and the Ayurvedic herb Leptadenia reticulata ^{14Reference 14Kumari S et al. · 2024ReviewA comprehensive review on ayurvedic herb Leptadenia reticulata (Jeevanti): a phytochemistry and pharmacological perspectiveView study →}. It is further reported from olive (Olea europaea), Teucrium species and vetch (Vicia).

Because it is nearly always glycosylated and rarely reported as the free aglycone, quantified free-diosmetin concentrations are scarce — most figures describe a specific glycoside in a specific tissue, so cross-source comparison is difficult ^{1,13Reference 1Patel K et al. · 2013ReviewA review on pharmacological and analytical aspects of diosmetin: a concise reportView study →Reference 13Posadino AM et al. · 2024ReviewCitrus limon var. pompia Camarda var. nova: A Comprehensive Review of Its Botanical Characteristics, Traditional Uses, Phytochemical Profile, and Potential Health BenefitsView study →}.

Discovery & Synthesis

Diosmetin entered the literature not on its own but as the aglycone of diosmin, a flavone glycoside named — like the buchu genus Diosma — from the Greek for “fragrant.” Diosmin was characterised in the early twentieth century; diosmetin is obtained from it by acid hydrolysis that removes the rutinose sugar ^{1,2Reference 1Patel K et al. · 2013ReviewA review on pharmacological and analytical aspects of diosmetin: a concise reportView study →Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}. Its structure is settled as 3’,5,7-trihydroxy-4’-methoxyflavone, i.e. luteolin methylated at the 4’-hydroxyl ^{6Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}.

Manufacture today is essentially an offshoot of diosmin production. Industrial diosmin is made semi-synthetically from hesperidin, the abundant citrus flavanone, which is extracted from citrus peel and chemically converted (dehydrogenation/oxidation) to diosmin ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}; diosmetin is then liberated by hydrolysing that diosmin. Direct extraction of the free aglycone from plants is not a significant commercial route because it is scarce and mostly glycosylated. The first total synthesis is not well documented.

Patents: not yet researched.

Toxicity & Safety

Diosmetin carries a low toxicity flag. As a minor flavone of common foods and herbs its dietary exposure is small, and as the aglycone of the widely used diosmin drug — which has a favourable clinical safety profile — the whole diosmin/diosmetin system is well tolerated in practice ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}. The cautions below are mostly theoretical, flowing from mechanism rather than from observed harm.

Safety at a Glance

✅ Low / no toxicityPhytoestrogenic

• Low dietary and drug-level toxicity. A minor food/herb flavone; the parent drug diosmin has a favourable clinical safety record ^{2Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →}.
• CYP1 (and other enzyme) inhibition — an interaction flag. Diosmetin potently inhibits CYP1A1/CYP1B1 in vitro, and diosmin inhibits several drug-metabolising enzymes; a theoretical basis for herb–drug interactions that has not been mapped in humans for the isolate ^{2,5,6Reference 2Gerges SH et al. · 2022ReviewPharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated ReviewView study →Reference 5Androutsopoulos VP et al. · 2011Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoidsView study →Reference 6Doostdar H et al. · 2000Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1View study →}.
• Weak phytoestrogen activity. Described as a phytoestrogen in the CYP1 cancer work — relevant context for hormone-sensitive settings, though effects are weak and unquantified in people ^{3Reference 3Androutsopoulos V et al. · 2009Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450View study →}.
• Evidence is preclinical. No human safety or toxicology dataset exists for isolated diosmetin; absence of reported harm is not the same as demonstrated safety.

No dedicated reproductive-toxicity dataset exists for isolated diosmetin. Pregnancy and lactation decisions belong to the herb or product page where intake is decided, not to this molecule page; the weak phytoestrogen and CYP-inhibition properties are noted above as cited mechanistic findings, not as a verdict.

Dosage

There is no established or recommended human dose for isolated diosmetin. In practice, human exposure to the molecule comes two ways:

Preclinical studies of the free molecule used research doses (e.g. 25–50 mg/kg orally in mice, tens of µM in cells) that do not convert to a human self-dose ^{7,8,9Reference 7Li HL et al. · 2022Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axisView study →Reference 8Lee DH et al. · 2020Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis modelView study →Reference 9He WS et al. · 2022Diosmetin inhibits apoptosis and activates AMPK-induced autophagy in myocardial damage under hypoxia environmentView study →}. These are figures from research and from the diosmin drug label, not a personal recommendation.

References

1. Patel K, Gadewar M, Tahilyani V, Patel DK (2013). A review on pharmacological and analytical aspects of diosmetin: a concise report. Chinese Journal of Integrative Medicine. https://pubmed.ncbi.nlm.nih.gov/24092244/
2. Gerges SH, Wahdan SA, Elsherbiny DA, El-Demerdash E (2022). Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review. European Journal of Drug Metabolism and Pharmacokinetics. https://pubmed.ncbi.nlm.nih.gov/34687440/
3. Androutsopoulos V, Wilsher N, Arroo RR, Potter GA (2009). Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450. Cancer Letters. https://pubmed.ncbi.nlm.nih.gov/18976853/
4. Androutsopoulos VP, Mahale S, Arroo RR, Potter G (2009). Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activation. Oncology Reports. https://pubmed.ncbi.nlm.nih.gov/19424633/
5. Androutsopoulos VP, Papakyriakou A, Vourloumis D, Spandidos DA (2011). Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoids. Bioorganic & Medicinal Chemistry. https://pubmed.ncbi.nlm.nih.gov/21482471/
6. Doostdar H, Burke MD, Mayer RT (2000). Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology. https://pubmed.ncbi.nlm.nih.gov/10781868/
7. Li HL, Wei YY, Li XH, et al. (2022). Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axis. Acta Pharmacologica Sinica. https://pubmed.ncbi.nlm.nih.gov/34262136/
8. Lee DH, Park JK, Choi J, Jang H, Seol JW (2020). Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model. International Immunopharmacology. https://pubmed.ncbi.nlm.nih.gov/33045572/
9. He WS, Wu Y, Ren MJ, Yu ZY, Zhao XS (2022). Diosmetin inhibits apoptosis and activates AMPK-induced autophagy in myocardial damage under hypoxia environment. The Kaohsiung Journal of Medical Sciences. https://pubmed.ncbi.nlm.nih.gov/34713558/
10. Si Q, Shi Y, Huang D, Zhang N (2020). Diosmetin alleviates hypoxia-induced myocardial apoptosis by inducing autophagy through AMPK activation. Molecular Medicine Reports. https://pubmed.ncbi.nlm.nih.gov/32627001/
11. Chen X, Xu L, Guo S, et al. (2019). Profiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSn. Journal of Chromatography B. https://pubmed.ncbi.nlm.nih.gov/31177049/
12. Hong SW, Teesdale-Spittle P, Page R, Truman P (2022). A review of monoamine oxidase (MAO) inhibitors in tobacco or tobacco smoke. Neurotoxicology. https://pubmed.ncbi.nlm.nih.gov/36155069/
13. Posadino AM, Maccioccu P, Eid AH, et al. (2024). Citrus limon var. pompia Camarda var. nova: A Comprehensive Review of Its Botanical Characteristics, Traditional Uses, Phytochemical Profile, and Potential Health Benefits. Nutrients. https://pubmed.ncbi.nlm.nih.gov/39203756/
14. Kumari S, Saini R, Bhatnagar A, Mishra A (2024). A comprehensive review on ayurvedic herb Leptadenia reticulata (Jeevanti): a phytochemistry and pharmacological perspective. Natural Product Research. https://pubmed.ncbi.nlm.nih.gov/37990540/
15. Mehreen A, Waheed M, Liaqat I, Arshad N (2016). Phytochemical, Antimicrobial, and Toxicological Evaluation of Traditional Herbs Used to Treat Sore Throat. BioMed Research International. https://pubmed.ncbi.nlm.nih.gov/27429983/

View all 15 references▾