Eupatorin

Pharmacology & Research

Eupatorin is a methoxylated flavone of the casticin/eupatilin/jaceosidin family, richest in java tea (Orthosiphon) and present in the flavonoid fractions of chaste-tree, tansy and feverfew. Its distinctive, honest hook is that it is partly a pro-drug: CYP1 enzymes (CYP1A1/1A2/1B1) bioactivate it by 4’-O-demethylation to cirsiliol and further-hydroxylated metabolites that are more cytotoxic than the parent, giving selective antiproliferative activity in CYP1-expressing cancer cells while sparing normal cells. That makes the anticancer story contingent on tissue CYP1 expression, not on dietary intake. All evidence is preclinical, and no human trial of the isolate exists.

1. Anticancer

The distinctive story: eupatorin is bioactivated by CYP1 enzymes to more cytotoxic metabolites, giving selective submicromolar potency in CYP1-expressing breast-cancer cells (MDA-MB-468) versus near-inactivity in normal MCF-10A cells ^{1,2Reference 1Androutsopoulos V et al. · 2008Antiproliferative and cytostatic effects of eupatorin on MDA-MB-468 breast cancer cells due to CYP1-mediated metabolismView study →Reference 2Androutsopoulos VP et al. · 2009CYP1-mediated antiproliferative activity of dietary flavonoids in MDA-MB-468 breast cancer cellsView study →}. Downstream it causes mitotic-checkpoint inactivation → polyploidy and G2/M arrest ^{3Reference 3Salmela AL et al. · 2012The flavonoid eupatorin inactivates the mitotic checkpoint, leading to polyploidy and apoptosisView study →}, caspase- and JNK-dependent, ROS-driven death in leukemia ^{6Reference 62014Eupatorin-induced cell death in human leukemia cells is dependent on caspases and activates the MAPK pathwayView study →}, and apoptosis/anti-angiogenesis in other breast lines ^{4Reference 4Razak NA et al. · 2019Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231 cells via cell-cycle arrest, anti-angiogenesis and apoptosisView study →}; one 4T1 mouse model reports tumour suppression with NF-κB downregulation ^{5Reference 5Nordin ML et al. · 2020AnimalEupatorin suppressed tumour progression and enhanced immunity in a 4T1 murine breast-cancer modelView study →}.

Gap: almost entirely cell-line data, with a single small animal model, no human data, and an effect contingent on CYP1 expression — so “anticancer” cannot be generalised to systemic dietary intake ^{1,5Reference 1Androutsopoulos V et al. · 2008Antiproliferative and cytostatic effects of eupatorin on MDA-MB-468 breast cancer cells due to CYP1-mediated metabolismView study →Reference 5Nordin ML et al. · 2020AnimalEupatorin suppressed tumour progression and enhanced immunity in a 4T1 murine breast-cancer modelView study →}.

2. Anti-inflammatory

Eupatorin (with sinensetin, from Orthosiphon stamineus) suppressed inflammatory gene expression (iNOS/NO, COX-2) and STAT1/NF-κB signalling in activated macrophages ^{7Reference 7Laavola M et al. · 2012Flavonoids eupatorin and sinensetin from Orthosiphon stamineus inhibit inflammatory gene expression and STAT1 activationView study →}, and one ovalbumin allergic-asthma mouse model showed reduced Th2 cytokines and airway inflammation ^{8Reference 82025AnimalEupatorin mitigates airway inflammation in ovalbumin-induced allergic asthma in mice by regulating Th2 cytokinesView study →}.

Gap: few studies in mixed models, with no isolate human data and mechanisms overlapping better-studied flavones ^{7,8Reference 7Laavola M et al. · 2012Flavonoids eupatorin and sinensetin from Orthosiphon stamineus inhibit inflammatory gene expression and STAT1 activationView study →Reference 82025AnimalEupatorin mitigates airway inflammation in ovalbumin-induced allergic asthma in mice by regulating Th2 cytokinesView study →}.

3. Vasorelaxant / diuretic

Eupatorin produced endothelium-dependent vasorelaxation of rat aortic rings (NO/cGMP, K⁺/Ca²⁺ channels) ^{9Reference 9Yam MF et al. · 2016AnimalMechanism of vasorelaxation induced by eupatorin in the rat aortic ringView study →} and reported synergy with sinensetin and a related tetramethoxyflavone ^{10Reference 102024Synergistic vasodilatory interaction of sinensetin, eupatorin and 3’-hydroxy-5,6,7,4’-tetramethoxyflavoneView study →}, supporting java tea’s traditional diuretic/antihypertensive reputation.

Gap: ex-vivo/isolated-tissue only, as one flavone among several actives, with no in-vivo blood-pressure or diuresis data for the isolate ^{9,10Reference 9Yam MF et al. · 2016AnimalMechanism of vasorelaxation induced by eupatorin in the rat aortic ringView study →Reference 102024Synergistic vasodilatory interaction of sinensetin, eupatorin and 3’-hydroxy-5,6,7,4’-tetramethoxyflavoneView study →}.

Mechanisms

Target / pathway	Effect	Relevant to
CYP1A1/1A2/1B1	substrate → bioactivation to cirsiliol + hydroxylated metabolites (selective cytotoxicity in CYP1-high cells)	anticancer; also pharmacokinetics
Mitotic checkpoint / tubulin apparatus	checkpoint inactivation → polyploidy, G2/M arrest, apoptosis	anticancer
Caspase cascade + JNK/MAPK, ROS	caspase-dependent, JNK-required, ROS-driven apoptosis	anticancer (leukemia)
NF-κB / STAT1; iNOS, COX-2, NO	suppressed inflammatory gene expression	anti-inflammatory; anticancer (in vivo)
NO/cGMP, K⁺/Ca²⁺ channels (endothelium)	vasorelaxation	vasorelaxant / diuretic
Estrogen receptor	weak (flavonoid-fraction level)	historical chaste-tree context

Pharmacokinetics

No dedicated pharmacokinetic study exists. As a lipophilic trimethoxy-dihydroxyflavone, eupatorin follows the general flavone pattern — reasonable passive cell entry in vitro but poor expected oral bioavailability in vivo (intestinal/hepatic first-pass metabolism, glucuronidation/sulfation). The mechanistically important point is CYP1 metabolism: CYP1 enzymes convert eupatorin to more cytotoxic metabolites ^{1,2Reference 1Androutsopoulos V et al. · 2008Antiproliferative and cytostatic effects of eupatorin on MDA-MB-468 breast cancer cells due to CYP1-mediated metabolismView study →Reference 2Androutsopoulos VP et al. · 2009CYP1-mediated antiproliferative activity of dietary flavonoids in MDA-MB-468 breast cancer cellsView study →}, so tissue CYP1 expression — not plasma parent concentration — likely governs activity, and CYP1A2 involvement raises theoretical drug-metabolism/interaction and chemoresistance considerations. In-vivo pharmacokinetics remain an open gap.

Clinical trials

There are no human trials of isolated eupatorin. Human exposure is only as a minor constituent of whole-plant preparations (chaste-tree extract; Orthosiphon stamineus/java tea), and all efficacy data are in-vitro or animal.

Last checked: July 2026.

Toxicity & Safety

Eupatorin has a low apparent toxicity — a dietary/medicinal methoxyflavone consumed for generations in java tea and other herbal preparations with no specific safety signal, and its preclinical cytotoxicity is selective for CYP1-expressing cancer cells, with normal cells markedly less affected ^{1,4Reference 1Androutsopoulos V et al. · 2008Antiproliferative and cytostatic effects of eupatorin on MDA-MB-468 breast cancer cells due to CYP1-mediated metabolismView study →Reference 4Razak NA et al. · 2019Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231 cells via cell-cycle arrest, anti-angiogenesis and apoptosisView study →}. No dedicated systemic toxicology, genotoxicity or repeat-dose study exists for the isolate, and the CYP1A2 interaction point is theoretical rather than a demonstrated harm.

Pregnancy & lactation

Avoid (isolated compound). There are no reproductive/developmental safety data for isolated eupatorin, and given the documented (weak) estrogen-receptor interaction of the chaste-tree flavonoid fraction ^{11Reference 11Wuttke W et al. · 2003Chaste tree (Vitex agnus-castus) — pharmacology and clinical indicationsView study →} and its antimitotic/pro-apoptotic activity in vitro, the isolate is not recommended in pregnancy or lactation. (Whole-herb amounts of the parent plants are governed by each herb’s own monograph.)

Dosage

There is no established human dose for isolated eupatorin, and none should be stated. Preclinical anchors only: in-vitro antiproliferative IC50 values are roughly submicromolar to low-micromolar in CYP1-expressing lines ^{1Reference 1Androutsopoulos V et al. · 2008Antiproliferative and cytostatic effects of eupatorin on MDA-MB-468 breast cancer cells due to CYP1-mediated metabolismView study →}, and the one in-vivo anticancer model used ~20 mg/kg in mice ^{5Reference 5Nordin ML et al. · 2020AnimalEupatorin suppressed tumour progression and enhanced immunity in a 4T1 murine breast-cancer modelView study →} — research figures, not human guidance.

References