The Sunlight Experiment

Compound Monograph

Hypophyllanthin

Hypophyllanthin is a lipophilic lignan that, with phyllanthin, standardises Phyllanthus niruri/amarus (chanca piedra). Preclinical only — an anti-inflammatory (NF-κB/MAPK/PI3K-Akt) and a distinctive in-vitro P-glycoprotein inhibitor / permeation enhancer — with no human isolate trials and poor aqueous solubility.

Work in progress

Classification

Hypophyllanthin is a lignan, part of the phenolics class. Antioxidant compounds built around one or more phenol rings — the flavonoids, tannins, phenolic acids, coumarins, and pigments behind much of a plant's protective chemistry.

Phenolics Lignans

Where Does It Come From? (2)

Hypophyllanthin is a naturally occurring lignan, found in Chanca Piedra and 1 other source. It is well tolerated orally (low toxicity).

Chanca Piedra Phyllanthus niruri Phyllanthus amarus and other Phyllanthus species

Pharmacology & Research

Hypophyllanthin is a lipophilic lignan that, with phyllanthin, serves as the species/standardisation marker of chanca piedra (Phyllanthus niruri/amarus). Two framing points. First, it partitions into alcohol, so it is enriched in tinctures/standardised extracts and scarce in aqueous tea — a preparation-discipline detail. Second, Phyllanthus’s hepatoprotective/kidney-stone reputation is the whole extract (and the phyllanthin marker), not isolated hypophyllanthin. Its own literature is preclinical and thin, with two genuine isolate signals: an anti-inflammatory action and — more distinctively — in-vitro P-glycoprotein inhibition, making it a candidate permeation enhancer and a drug-interaction concern.

What the evidence supports
  • A distinctive P-glycoprotein/permeation-enhancer signal: hypophyllanthin inhibited P-gp efflux (not MRP2) in Caco-2 cells and sensitised doxorubicin-resistant cancer cells 2,5Reference 2Sukhaphirom N et al. · 2013Phyllanthin and hypophyllanthin inhibit the function of P-gp but not MRP2 in Caco-2 cellsView study →Reference 5Abdel-Sattar OE et al. · 2023Hypophyllanthin and phyllanthin from Phyllanthus niruri synergise doxorubicin’s anticancer properties against resistant breast-cancer cellsView study →.
  • The honest headline: no human isolate trials; the anti-inflammatory studies pair it with a second lignan; and the hepatoprotective reputation belongs to the whole Phyllanthus extract, not this molecule 3,9Reference 3Harikrishnan H et al. · 2018Anti-inflammatory effects of hypophyllanthin and niranthin through downregulation of NF-κB/MAPK/PI3K-Akt signallingView study →Reference 9Al Zarzour RH et al. · 2017Phyllanthus niruri standardised extract alleviates the progression of non-alcoholic fatty liver diseaseView study →.
Evidence by indicationStrength of support
Anti-InflammatoryShaky
28%
Bioavailability / P-GlycoproteinShaky
26%
Hepatoprotective (Phyllanthus Rationale)Unsupported
18%
AntihyperuricemicUnsupported
12%
1. Anti-inflammatory

Hypophyllanthin (with niranthin) downregulated NF-κB, the MAPKs (ERK/JNK/p38) and PI3K-Akt in LPS-stimulated macrophages 3Reference 3Harikrishnan H et al. · 2018Anti-inflammatory effects of hypophyllanthin and niranthin through downregulation of NF-κB/MAPK/PI3K-Akt signallingView study →, and the phyllanthin+hypophyllanthin pair reduced IgE/iNOS/TNF-α and raised Nrf2 in ovalbumin-induced asthma 4Reference 4Wu W et al. · 2019Phyllanthin and hypophyllanthin from Phyllanthus amarus ameliorate the immune-inflammatory response in ovalbumin-induced asthmaView study →, consolidated in a 2022 review 1Reference 1Wan Saidin WA et al. · 2022ReviewPharmacological activities and mechanisms of action of hypophyllanthin: a reviewView study →.

Gap: each study pairs it with a second lignan or uses different models, with no single target replicated for hypophyllanthin alone and only downstream readouts 3,4Reference 3Harikrishnan H et al. · 2018Anti-inflammatory effects of hypophyllanthin and niranthin through downregulation of NF-κB/MAPK/PI3K-Akt signallingView study →Reference 4Wu W et al. · 2019Phyllanthin and hypophyllanthin from Phyllanthus amarus ameliorate the immune-inflammatory response in ovalbumin-induced asthmaView study →.

2. Bioavailability / P-glycoprotein

The distinctive detail: phyllanthin and hypophyllanthin inhibited P-glycoprotein efflux (but not MRP2) in Caco-2 cells 2Reference 2Sukhaphirom N et al. · 2013Phyllanthin and hypophyllanthin inhibit the function of P-gp but not MRP2 in Caco-2 cellsView study →, and consistent with this, the pair sensitised doxorubicin-resistant breast-cancer cells 5Reference 5Abdel-Sattar OE et al. · 2023Hypophyllanthin and phyllanthin from Phyllanthus niruri synergise doxorubicin’s anticancer properties against resistant breast-cancer cellsView study → — making hypophyllanthin a candidate absorption/permeation enhancer and a drug-interaction concern 7Reference 7Dash RP et al. · 2017Implication of formulation strategies on the bioavailability of selected plant-derived hepatoprotectantsView study →.

Gap: in-vitro only, with no in-vivo interaction or human pharmacokinetic confirmation 2,5Reference 2Sukhaphirom N et al. · 2013Phyllanthin and hypophyllanthin inhibit the function of P-gp but not MRP2 in Caco-2 cellsView study →Reference 5Abdel-Sattar OE et al. · 2023Hypophyllanthin and phyllanthin from Phyllanthus niruri synergise doxorubicin’s anticancer properties against resistant breast-cancer cellsView study →.

3. Hepatoprotective (Phyllanthus rationale)

Liver protection is the traditional Phyllanthus indication, but the evidence is for the whole extract/genus (and, as a marker, phyllanthin), including NAFLD 9Reference 9Al Zarzour RH et al. · 2017Phyllanthus niruri standardised extract alleviates the progression of non-alcoholic fatty liver diseaseView study → and broader hepatoprotection 10Reference 10Srirama R et al. · 2012Hepatoprotective activity of Indian PhyllanthusView study →.

Gap: there is no isolated-hypophyllanthin hepatoprotection study — it rides on marker/extract co-attribution 9,10Reference 9Al Zarzour RH et al. · 2017Phyllanthus niruri standardised extract alleviates the progression of non-alcoholic fatty liver diseaseView study →Reference 10Srirama R et al. · 2012Hepatoprotective activity of Indian PhyllanthusView study →.

4. Antihyperuricemic

Hypophyllanthin is a weak xanthine-oxidase inhibitor and a uricosuric lignan 6Reference 6Murugaiyah V · 2009Mechanisms of the antihyperuricemic effect of Phyllanthus niruri and its lignan constituentsView study →.

Gap: a weak effect resting on a single mechanistic paper for the isolate 6Reference 6Murugaiyah V · 2009Mechanisms of the antihyperuricemic effect of Phyllanthus niruri and its lignan constituentsView study →.

Mechanisms

Target / pathwayEffectRelevant to
NF-κB / MAPK (ERK, JNK, p38) / PI3K-Aktdownregulated → ↓ iNOS, COX-2, cytokinesanti-inflammatory
Nrf2 ↑; IgE, iNOS, TNF-α ↓immune-inflammatory modulationanti-allergic / asthma
P-glycoprotein (ABCB1) effluxinhibited (MRP2 unaffected) → ↑ intracellular substratebioavailability / permeation, MDR reversal
Xanthine oxidaseweak inhibition; uricosuricantihyperuricemic

Pharmacokinetics

Hypophyllanthin is a lipophilic aryltetralin-type lignan with poor aqueous solubility and low oral bioavailability — it partitions into alcohol, so it is enriched in tinctures/standardised extracts and scarce in aqueous tea. Formulation strategies to raise solubility/absorption have been reviewed for this hepatoprotectant class 7Reference 7Dash RP et al. · 2017Implication of formulation strategies on the bioavailability of selected plant-derived hepatoprotectantsView study →, and a validated LC-MS/MS method quantifies it (with co-lignans) in rat plasma 8Reference 8Fan H et al. · 2015AnimalHPLC-MS/MS method for the determination of four lignans from Phyllanthus urinaria in rat plasmaView study →. As a P-gp inhibitor 2Reference 2Sukhaphirom N et al. · 2013Phyllanthin and hypophyllanthin inhibit the function of P-gp but not MRP2 in Caco-2 cellsView study →, hypophyllanthin may increase absorption of itself and of co-administered P-gp substrates — a two-way drug-interaction signal, in-vitro only — and there is no human pharmacokinetic data.

Clinical trials

There are no trials of isolated hypophyllanthin. Human Phyllanthus trials (kidney stones; chronic hepatitis B) use the whole extract, where hypophyllanthin serves only as a standardisation/identity marker, not as the studied agent.

CompletedPlannedTerminatedPreclinical
—(none, isolate)——Thin(mostly paired with a co-lignan)

Last checked: July 2026.

Toxicity & Safety

Hypophyllanthin has a low-concern profile with no isolate toxicity signal identified, so the [low] flag reflects sparse dedicated data rather than demonstrated safety. A drug-interaction caution is warranted on mechanistic grounds — its in-vitro P-glycoprotein inhibition 2Reference 2Sukhaphirom N et al. · 2013Phyllanthin and hypophyllanthin inhibit the function of P-gp but not MRP2 in Caco-2 cellsView study → could raise the absorption of narrow-therapeutic-index P-gp substrates — but this is in-vitro/theoretical, not clinically documented.

Pregnancy & lactation

Avoid. There are no data on the isolated compound, and Phyllanthus species carry a traditional caution in pregnancy — with the isolate unstudied, it is best avoided in pregnancy and lactation.

Dosage

There is no human dose established — hypophyllanthin is a marker/standardisation constituent, not a standalone supplement, and all data are preclinical, so nothing here is a recommendation.

References

  1. Wan Saidin WA, et al. (2022). Pharmacological activities and mechanisms of action of hypophyllanthin: a review. Frontiers in Pharmacology. https://pubmed.ncbi.nlm.nih.gov/36699081/
  2. Sukhaphirom N, et al. (2013). Phyllanthin and hypophyllanthin inhibit the function of P-gp but not MRP2 in Caco-2 cells. Journal of Pharmacy and Pharmacology. https://pubmed.ncbi.nlm.nih.gov/23278697/
  3. Harikrishnan H, et al. (2018). Anti-inflammatory effects of hypophyllanthin and niranthin through downregulation of NF-κB/MAPK/PI3K-Akt signalling. Inflammation. https://pubmed.ncbi.nlm.nih.gov/29427163/
  4. Wu W, et al. (2019). Phyllanthin and hypophyllanthin from Phyllanthus amarus ameliorate the immune-inflammatory response in ovalbumin-induced asthma. Immunopharmacology and Immunotoxicology. https://pubmed.ncbi.nlm.nih.gov/30541359/
  5. Abdel-Sattar OE, et al. (2023). Hypophyllanthin and phyllanthin from Phyllanthus niruri synergise doxorubicin’s anticancer properties against resistant breast-cancer cells. ACS Omega. https://pubmed.ncbi.nlm.nih.gov/37576627/
  6. Murugaiyah V, Chan KL (2009). Mechanisms of the antihyperuricemic effect of Phyllanthus niruri and its lignan constituents. Journal of Ethnopharmacology. https://pubmed.ncbi.nlm.nih.gov/19397979/
  7. Dash RP, et al. (2017). Implication of formulation strategies on the bioavailability of selected plant-derived hepatoprotectants. Critical Reviews in Therapeutic Drug Carrier Systems. https://pubmed.ncbi.nlm.nih.gov/29256835/
  8. Fan H, et al. (2015). HPLC-MS/MS method for the determination of four lignans from Phyllanthus urinaria in rat plasma. Bioanalysis. https://pubmed.ncbi.nlm.nih.gov/25871587/
  9. Al Zarzour RH, et al. (2017). Phyllanthus niruri standardised extract alleviates the progression of non-alcoholic fatty liver disease. Nutrients. https://pubmed.ncbi.nlm.nih.gov/28718838/
  10. Srirama R, et al. (2012). Hepatoprotective activity of Indian Phyllanthus. Pharmaceutical Biology. https://pubmed.ncbi.nlm.nih.gov/22480277/