Retrorsine (Pyrrolizidine Alkaloid · Hepatotoxic · Research Reference)
| Compound | Retrorsine (Isatidine; 12-Hydroxysenecionan-11,16-dione; macrocyclic PA) |
| Class | Alkaloid — Pyrrolizidine (Macrocyclic diester, retronecine type) |
| CAS | 480-54-6 |
| Molecular formula | C₁₈H₂₅NO₆ |
| Primary sources | Senecio isatideus, Senecio retrorsus, Crotalaria spp. |
| Plant part | Aerial parts, seeds |
| Claim strength | Emerging (toxicology) |
| Key applications | Hepatotoxicity research model; pyrrolizidine alkaloid reference; veno-occlusive disease; informational-only |
| Buy from Herbuno | Informational reference — see HerbIQ Compound Index → |
Name origin: Retrorsine is named after Senecio retrorsus (now reclassified), the South African Senecio species from which it was originally isolated. The systematic name reflects its retronecine necine base (the bicyclic pyrrolizidine alcohol) esterified with two necic acid groups in a macrocyclic diester pattern. Traditional context: Retrorsine is not a traditional medicine compound — it is a toxic pyrrolizidine alkaloid (PA) produced by its source plants as a feeding deterrent. Senecio species are among the most common plants responsible for livestock and human PA poisoning globally. The hepatotoxicity of certain Senecio preparations (some accidentally consumed in herbal teas or grain contamination) is attributable primarily to macrocyclic PAs including retrorsine. Research trajectory: Retrorsine gained significant research importance as a hepatotoxicity model compound — it selectively destroys hepatocytes while sparing oval cells (hepatic progenitor cells), creating a partial hepatectomy-like model used to study liver regeneration and stem cell biology. This retrorsine partial hepatectomy model has been instrumental in xenobiotic liver repopulation research and is still used in translational hepatology. Safety context: Retrorsine is a confirmed hepatotoxin and genotoxin. Its metabolic activation to dehydroretronecine pyrroles by CYP3A4 creates DNA-crosslinking alkylating species. It is not present in any commercial herbal preparation and has no supplemental or therapeutic application.
Toxicological Profile of Retrorsine
Hepatotoxicity mechanism: CYP3A4 and CYP2B6 oxidise retrorsine to the reactive pyrrolic ester dehydroretronecine (DHR), which forms DNA and protein adducts in hepatocytes. Repeated low-dose exposure causes sinusoidal obstruction syndrome (formerly veno-occlusive disease — VOD) — obstruction of hepatic sinusoids and central veins leading to progressive hepatic necrosis. The Budd-Chiari-like syndrome observed in PA poisoning is pathognomonic. Claim strength: High (toxicology).
Genotoxicity: DHR pyrroles are bifunctional alkylating agents that form interstrand DNA crosslinks — classified as genotoxic in Ames testing and mammalian cell mutagenicity assays. Retrorsine has been classified as a possible human carcinogen (IARC Group 2B) by association with PA class genotoxicity. Claim strength: High (toxicology).
Research model utility: The retrorsine/partial hepatectomy model (Laconi 1995) exploits retrorsine's selective hepatocyte toxicity to create a regenerative niche for transplanted normal hepatocytes or stem cells. Retrorsine-treated rats can be repopulated with >90% donor hepatocytes — a key tool for cell therapy and xenobiotic metabolism research. Claim strength: High (experimental biology).
Regulatory context: European Food Safety Authority (EFSA) has established PA maximum limits for food and herbal products (including herbal teas, supplements, honey, and pollen) across all PA congeners including macrocyclic types. Retrorsine itself is excluded from consumer products; regulatory limits target total PA burden in products that may be accidentally contaminated. Claim strength: High (regulatory).
This compound is documented for research and formulator education purposes. For commercially available botanical ingredients, explore the HerbIQ Compound Index →
Regulatory and Safety Context for Formulators
Retrorsine has no application in dietary supplements, cosmetics, or food. The critical regulatory issue for formulators is the inadvertent PA contamination of botanical raw materials — particularly comfrey (Symphytum), borage (Borago), coltsfoot (Tussilago), and products from Senecio-contaminated grain.
EFSA's 2016 scientific opinion on PAs established a margin of exposure (MOE) approach, with retrorsine among the most genotoxically concerning macrocyclic PAs. EU regulations now require PA monitoring in herbs sold as food supplements and botanical preparations used in food. Current EU maximum levels for total PAs in herbal infusion products are 0.35 μg/kg (2022 amendment).
Formulators sourcing Borago officinalis, Symphytum, or any Senecio-family botanical should require PA testing (LC-MS/MS, minimum 28-PA panel per EFSA) from suppliers. Herbuno's botanical extracts are sourced with quality documentation requirements addressing contamination risk.
The hepatotoxicity of retrorsine and related macrocyclic PAs is irreversible at sufficient exposure — there is no antidote beyond supportive care. This makes supplier quality assurance and botanical identification paramount for consumer product safety.
Frequently Asked Questions — Retrorsine
What is pyrrolizidine alkaloid (PA) poisoning and how does retrorsine cause it?
PA poisoning occurs when macrocyclic PAs from plants (Senecio, Heliotropium, Crotalaria, Symphytum) are consumed — typically via contaminated grain, herbal preparations, or bush tea. Liver CYP enzymes convert PAs to reactive pyrrolic esters (dehydroalkaloids) that alkylate DNA and proteins in hepatocytes, causing sinusoidal obstruction syndrome — initially presenting as abdominal pain and ascites, progressing to hepatic failure. Retrorsine is one of the most genotoxically potent macrocyclic PAs used to model this condition.
Which commercially important herbs are potential PA contamination sources?
The primary food supplement contamination concerns are: borage (Borago officinalis) products — lycopsamine, thesinine; comfrey (Symphytum officinale) — symphytine, echimidine; coltsfoot (Tussilago farfara) — senkirkine, integerrimine; and cross-contamination of herbal teas with Senecio species. EU and US regulatory agencies have issued specific warnings and limits for these. Retrorsine specifically is not found in these commercial herbs at significant concentrations — it is a marker compound for Senecio isatideus and related species not used commercially.
How is the retrorsine liver model used in regenerative medicine research?
Retrorsine (given in 2 doses, 30 mg/kg, 2 weeks apart) selectively blocks hepatocyte proliferation without killing cells. When these retrorsine-treated rats undergo 2/3 partial hepatectomy, the normal regenerative response is blocked in host hepatocytes but not in transplanted donor hepatocytes. This creates a selective growth advantage for transplanted cells, allowing liver repopulation to >70–90%. The model has been used to study hepatocyte transplantation, induced pluripotent stem cell-derived hepatocyte engraftment, and gene therapy for liver diseases.
What PA testing should formulators require for borage and comfrey-containing products?
EFSA recommends minimum 28 PA congener panels by LC-MS/MS. For borage seed oil and borage supplements, the primary PAs to test are lycopsamine, thesinine, and intermedine. For comfrey root, symphytine, echimidine, and lasiocarpine are the priority markers. Total PA burden in the finished product should be assessed against EFSA MOE benchmarks; EU maximum levels (0.35 μg/kg for herbal infusions) provide a reference standard for consumer product compliance.
Related compounds: Lasiocarpine, Lycopsamine, Senkirkine, Platyphylline
Claim-strength scale – High = multiple human RCTs; Moderate = limited trials or strong preclinical convergence; Emerging = early-stage lab or animal data.
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