Rutacridone

Rutacridone at a Glance

Rutacridone is the principal acridone alkaloid of rue’s roots, and the first thing to say about it is the mutagenicity. In the Salmonella/microsome assay rutacridone is a promutagen: it requires rat liver enzymes to become mutagenic, and the evidence points to conversion into rutacridone epoxide as the ultimate mutagen — a compound that is mutagenic without any metabolic activation at all, in S. typhimurium TA98, TA100 and TA1538 ^{2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →}.

The same epoxide is the reason the molecule has an agricultural literature. In bioassay-guided fractionation of rue root, rutacridone epoxide was selectively algicidal against the taste-and-odour cyanobacterium Oscillatoria perornata and more active than the commercial fungicides captan and benomyl against Colletotrichum, Botrytis and Fusarium pathogens. It was never developed, and the paper reporting the activity says why in the same paragraph: it is a direct-acting mutagen, “precluding its use as an agrochemical” ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}.

Rutacridone has no medicinal use, no human data and no isolate toxicology beyond the bacterial assays.

Rutacridone Versus Rutacridone Epoxide

Almost every interesting property attributed to “rutacridone” belongs to its epoxide, and the two are separate compounds with different behaviour. Keeping them apart is the whole of the story.

Rutacridone is a dihydrofuroacridone — an acridone core with a fused dihydrofuran ring bearing an isopropenyl group, absolute configuration 2′(R) ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}. Rutacridone epoxide is the same skeleton with that side-chain double bond epoxidised, configuration 2′(R),3′(R) ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}. The plant makes both, and mammalian liver makes the second from the first.

	Rutacridone	Rutacridone epoxide
Mutagenicity	promutagen — needs S9 activation 2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →	direct-acting mutagen in TA98, TA100, TA1538 2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →
Effect of adding liver preparations	activates it	markedly decreases mutagenicity 2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →
Antifungal / algicidal activity	not the active compound	potent; beats captan and benomyl 1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →
In the plant	dominant root alkaloid 5Reference 5Kuzovkina I et al. · 2004In vitroSpecific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens — in vitroView study →	minor, but strongly elicitor-inducible 6Reference 6Eilert U et al. · 1984In vitroElicitor-induced accumulation of acridone alkaloid epoxides in Ruta graveolens suspension cultures — in vitroView study →

Two details in that table are worth dwelling on. First, liver preparations move the two compounds in opposite directions — activating the parent, deactivating the epoxide — which is exactly what you expect if the parent is converted to the epoxide and the epoxide is then detoxified by hydrolases and glutathione transferases ^{2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →}.

Second, the epoxide’s potency and its genotoxicity are the same chemistry. An epoxide is an electrophile: it alkylates whatever nucleophile it meets, which in a fungus is a useful thing and in DNA is a mutation. Synthetic analogues built around the same (2-methyloxiranyl)-dihydrobenzofuran motif, made specifically to try to separate the two, were all less active than the natural compound ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}. There is no version of this molecule that keeps the fungicide and drops the mutagen.

There is also a genuinely odd protective finding: eight furocoumarins from the same plant — including bergapten and imperatorin — suppressed the mutagenicity of rutacridone and dictamnine in TA98 in a dose-dependent way, most likely by inactivating the P450s that would otherwise activate them ^{3Reference 3Schimmer O et al. · 1991In vitroInhibitory effects of furocoumarins in Salmonella typhimurium TA98 on the mutagenicity of dictamnine and rutacridone, promutagens from Ruta graveolens L. — in vitroView study →}. Rue’s own furanocoumarins, in other words, partially disarm its own promutagens in a bacterial assay. It is a striking result about a whole-plant matrix, and it is not a safety argument for consuming rue root.

What It's Used For

There is no pharmacology in the ordinary sense — no receptor, no clinical indication, no animal efficacy study. What exists is genetic toxicology, an agrochemical screen, and one antiproliferative panel in which rutacridone was not the interesting compound.

Evidence by IndicationStrength of support · Beta

01GenotoxicityPromising46%Full Salmonella/microsome study with multiple activation systems, plus a follow-up on inhibition ^{2,3Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →Reference 3Schimmer O et al. · 1991In vitroInhibitory effects of furocoumarins in Salmonella typhimurium TA98 on the mutagenicity of dictamnine and rutacridone, promutagens from Ruta graveolens L. — in vitroView study →}

02Antifungal & algicidalShaky32%Bioassay-guided isolation with commercial-fungicide comparators and synthetic analogues ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}

03AntiproliferativeShaky12%One breast-cancer panel in which this compound was among the weaker of six ^{4Reference 4Schelz Z et al. · 2016In vitroAntiproliferative effects of various furanoacridones isolated from Ruta graveolens on human breast cancer cell lines — in vitroView study →}

Mechanisms

Pharmacokinetics

Nothing is known. No absorption, distribution, metabolism or excretion study of rutacridone exists in any species. The only metabolic fact in hand is qualitative and comes from the mutagenicity work: rat liver enzymes epoxidise it, and the resulting epoxide is then deactivated by hydrolytic and cytosolic pathways ^{2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →}. Whether rutacridone is meaningfully absorbed from an oral rue preparation is unknown, and no measurement of its concentration in any commercial rue product was found.

Clinical Trials

None, and none is conceivable for a promutagen with no therapeutic hypothesis.

Last checked: September 2026.

Isolate vs. Plant Studies

Every result here is isolate work — purified rutacridone or purified rutacridone epoxide, tested in defined assays ^{1,2,3,4Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →Reference 3Schimmer O et al. · 1991In vitroInhibitory effects of furocoumarins in Salmonella typhimurium TA98 on the mutagenicity of dictamnine and rutacridone, promutagens from Ruta graveolens L. — in vitroView study →Reference 4Schelz Z et al. · 2016In vitroAntiproliferative effects of various furanoacridones isolated from Ruta graveolens on human breast cancer cell lines — in vitroView study →}. There is no whole-extract counterpart and no animal or human study of either compound.

The reason this matters practically is the plant part. Acridone alkaloids concentrate in rue’s roots, while the furanocoumarins that dominate its safety reputation sit in the aerial parts. Rue preparations are normally made from the herb rather than the root, so the exposure most people receive is not the one described here — and the root-based products that would deliver it are the ones the genotoxicity argues against. The one whole-matrix finding available cuts in the plant’s favour and should not be over-read: co-occurring furocoumarins inhibited rutacridone’s mutagenicity in a bacterial assay ^{3Reference 3Schimmer O et al. · 1991In vitroInhibitory effects of furocoumarins in Salmonella typhimurium TA98 on the mutagenicity of dictamnine and rutacridone, promutagens from Ruta graveolens L. — in vitroView study →}, which is a statement about competing P450 substrates, not about human safety.

Its Role in Plants

Rutacridone looks like a phytoalexin — a defence compound made on demand rather than stored. In Ruta graveolens suspension cultures the epoxides (rutacridone epoxide and hydroxyrutacridone epoxide) were present at only 1–50 µg/g dry weight under normal conditions, but rose up to a hundredfold within 72 hours when the cultures were elicited with live or immobilised yeast, dead Rhodotorula rubra cells, or crude fungal cell wall. Chitosan and alginate barely worked, and arachidonic and elaidic acid did nothing. Notably, elicitation raised the epoxides without raising rutacridone itself ^{6Reference 6Eilert U et al. · 1984In vitroElicitor-induced accumulation of acridone alkaloid epoxides in Ruta graveolens suspension cultures — in vitroView study →} — an induced-defence response that produces the electrophile specifically.

Within the root, distribution is fine-grained: acridone alkaloids give rue’s root tips a strong autofluorescence, and HPLC-NMR of transformed root cultures found rutacridone dominant in the elongation and differentiation zones, with gravacridondiol glucoside the dominant compound of the root tip itself ^{5Reference 5Kuzovkina I et al. · 2004In vitroSpecific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens — in vitroView study →}.

Biosynthetically it is a quinoline-family alkaloid: feeding studies in rue tissue culture showed anthranilic acid is specifically incorporated into ring A, with acetate contributing via a polyketide, while mevalonate was poorly incorporated — leaving the origin of the isopropyl-dihydrofuran moiety unresolved ^{7Reference 7Baumert A et al. · 1982In vitroBiosynthesis of rutacridone in tissue cultures of Ruta graveolens L. — in vitroView study →}. A separate study worked out the N-methylation step ^{8Reference 8Baumert A et al. · 1983In vitroBiosynthesis of rutacridone: the N-methylation step — in vitroView study →}.

Prevalence in Nature

Rutacridone is essentially a Ruta graveolens compound. It is the main acridone alkaloid of rue root and the dominant alkaloid of rue tissue and transformed-root cultures ^{5,7Reference 5Kuzovkina I et al. · 2004In vitroSpecific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens — in vitroView study →Reference 7Baumert A et al. · 1982In vitroBiosynthesis of rutacridone in tissue cultures of Ruta graveolens L. — in vitroView study →}, and it belongs to a wider acridone and furanoacridone series in the same plant — gravacridondiol, gravacridonetriol, their glucosides and monomethyl ethers, arborinine, and isogravacridone chlorine ^{4,5Reference 4Schelz Z et al. · 2016In vitroAntiproliferative effects of various furanoacridones isolated from Ruta graveolens on human breast cancer cell lines — in vitroView study →Reference 5Kuzovkina I et al. · 2004In vitroSpecific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens — in vitroView study →}.

Acridone alkaloids as a class are a Rutaceae speciality, and rue is one of their best-studied sources. No reliable field-material percentage for rutacridone was found; the quantified figures available are for tissue culture ^{6Reference 6Eilert U et al. · 1984In vitroElicitor-induced accumulation of acridone alkaloid epoxides in Ruta graveolens suspension cultures — in vitroView study →}, so no per-source comparison can be drawn.

Discovery & Synthesis

Rutacridone was reported from Ruta graveolens in 1967 by Reisch and colleagues ^{9Reference 9Reisch J et al. · 1967Rutacridone from Ruta graveolensView study →}. Its absolute configuration was not settled until 2005, when circular dichroism and NMR established rutacridone as 2′(R) and rutacridone epoxide as 2′(R),3′(R) ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}.

There is no commercial synthesis and no commercial production. The only synthetic work on the skeleton was a deliberate attempt to build safer analogues of the epoxide by retaining the (2-methyloxiranyl)-dihydrobenzofuran motif; none matched the natural compound’s activity ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}. Material for research comes from rue root or, more conveniently, from genetically transformed root cultures, where it accumulates as the major alkaloid ^{5Reference 5Kuzovkina I et al. · 2004In vitroSpecific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens — in vitroView study →}.

Patents: not yet researched (future patent-loop pass).

Toxicity & Safety

Rutacridone’s flag is moderate, and it is a genotoxicity flag rather than an acute-toxicity one — there is no acute toxicity data at all.

Safety at a Glance

⚠️ Moderate toxicity

• A promutagen. Rutacridone becomes mutagenic after metabolic activation, and the activated species — rutacridone epoxide — is mutagenic in three Salmonella strains with no activation needed ^{2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →}.
• Its useful activity and its genotoxicity are one chemistry. The epoxide that beat captan and benomyl as a fungicide is the same electrophile that alkylates DNA; analogues designed to separate them failed ^{1Reference 1Meepagala KM et al. · 2005In vitroAlgicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitroView study →}.
• Root material is the exposure that matters. Acridones concentrate in rue’s roots, not the aerial parts most preparations use.
• No mammalian toxicology whatsoever. No repeat-dose, carcinogenicity, reproductive or human data exist. “Moderate” here reflects a hazard signal and an empty dataset, not a measured risk.

Full Safety & Interactions Detail

What was actually shown. The genotoxicity finding is a standard, well-conducted Ames-type study using multiple activation systems and enzyme inhibitors, and its conclusion is specific: rutacridone is metabolised by rat liver enzymes to the corresponding epoxide as the ultimate mutagen ^{2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →}. The epoxide’s own mutagenicity is direct-acting, and decreases when liver preparations are added, consistent with enzymatic detoxification of the electrophile ^{2Reference 2Paulini H · 1989In vitroMutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitroView study →}.

What was not shown. Bacterial mutagenicity is a hazard identification, not a risk assessment. No mammalian genotoxicity assay, no carcinogenicity bioassay, no repeat-dose toxicity study and no exposure measurement exist for either compound, so nothing here supports a numerical statement of risk from any rue product. Equally, nothing supports treating the signal as unimportant: this is a molecule whose metabolite damages DNA without needing to be activated.

Where it sits within rue’s safety story. Rue’s better-known hazards are its furanocoumarin phototoxicity and its abortifacient action — the latter traced to chalepensin, a coumarin from the aerial parts. Rutacridone is a third, separate concern, attached to the root, and it is the reason root-based rue preparations warrant more caution than the aerial-parts ones. Note also the interaction finding in the opposite direction: rue’s furanocoumarins inhibit the P450s that activate rutacridone ^{3Reference 3Schimmer O et al. · 1991In vitroInhibitory effects of furocoumarins in Salmonella typhimurium TA98 on the mutagenicity of dictamnine and rutacridone, promutagens from Ruta graveolens L. — in vitroView study →}, so the promutagen and its inhibitor occur in the same plant — an interesting result about whole-matrix chemistry that should not be read as protection.

Interactions. Not assessed. No cytochrome-P450 inhibition or induction study of rutacridone was found.

Dosage

There is no dose. Rutacridone has never been administered to an animal or a person for any purpose, and given the genotoxicity there is no plausible reason to. The concentrations that appear in the literature are assay figures — micromolar in cell panels ^{4Reference 4Schelz Z et al. · 2016In vitroAntiproliferative effects of various furanoacridones isolated from Ruta graveolens on human breast cancer cell lines — in vitroView study →}, and microgram-per-gram tissue levels in culture ^{6Reference 6Eilert U et al. · 1984In vitroElicitor-induced accumulation of acridone alkaloid epoxides in Ruta graveolens suspension cultures — in vitroView study →}. These are research measurements, not a personal recommendation.

References

1. Meepagala KM, Schrader KK, Wedge DE, Duke SO (2005). Algicidal and antifungal compounds from the roots of Ruta graveolens and synthesis of their analogs — in vitro. Phytochemistry. https://pubmed.ncbi.nlm.nih.gov/16271733/
2. Paulini H, Schimmer O (1989). Mutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/microsome assay — in vitro. Mutagenesis. https://pubmed.ncbi.nlm.nih.gov/2654551/
3. Schimmer O, Kiefer J, Paulini H (1991). Inhibitory effects of furocoumarins in Salmonella typhimurium TA98 on the mutagenicity of dictamnine and rutacridone, promutagens from Ruta graveolens L. — in vitro. Mutagenesis. https://pubmed.ncbi.nlm.nih.gov/1800898/
4. Schelz Z, Ocsovszki I, Bózsity N, Hohmann J, Zupkó I (2016). Antiproliferative effects of various furanoacridones isolated from Ruta graveolens on human breast cancer cell lines — in vitro. Anticancer Research. https://pubmed.ncbi.nlm.nih.gov/27272785/
5. Kuzovkina I, Al’terman I, Schneider B (2004). Specific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens — in vitro. Phytochemistry. https://pubmed.ncbi.nlm.nih.gov/15110689/
6. Eilert U, Ehmke A, Wolters B (1984). Elicitor-induced accumulation of acridone alkaloid epoxides in Ruta graveolens suspension cultures — in vitro. Planta Medica. https://pubmed.ncbi.nlm.nih.gov/17340365/
7. Baumert A, Kuzovkina IN, Krauss G, Hieke M, Gröger D (1982). Biosynthesis of rutacridone in tissue cultures of Ruta graveolens L. — in vitro. Plant Cell Reports. https://pubmed.ncbi.nlm.nih.gov/24259136/
8. Baumert A, Kuzovkina IN, Hieke M, et al. (1983). Biosynthesis of rutacridone: the N-methylation step — in vitro. Planta Medica. https://pubmed.ncbi.nlm.nih.gov/17404973/
9. Reisch J, Szendrei K, Minker E, et al. (1967). Rutacridone from Ruta graveolens. Acta Pharmaceutica Suecica. https://pubmed.ncbi.nlm.nih.gov/6082978/

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