Zi Cao
StarLithospermum erythrorhizon Sieb. et Zucc.; Arnebia euchroma (Royle) Johnst.
Traditionally used for
- Bowel health
- Skin
Cautions & contraindications
- Pregnancy
- Young children
- Liver conditions
☯ TCM Properties
Cools the Blood; Resolves Toxicity; Vents Rashes; Invigorates Blood and Dispels Stasis; Moistens the Intestines and Unblocks the Bowels
Traditional Chinese Uses
Zi Cao (gromwell root) is a cold herb that cools the Blood and clears Heat toxin, with particular utility in treating conditions where Heat has entered the Blood level. It is a key herb for measles and rashes that are slow to erupt or appear purplish — indicating trapped heat in the blood. Topically it is used for burns, skin ulcers, and inflammatory skin conditions. Modern preparations for wounds and eczema continue its traditional external application.
Pharmacological Effects
- Antibacterial and antiinflammatory: Ether/petroleum ether fractions of L. erythrorhizon inhibited Gram-positive bacteria; β,β-dimethylacrylshikonin was antiinflammatory in intact and adrenalectomized rats (paw edema, cotton pellet granuloma, capillary permeability); shikonin and acetylshikonin inhibited histamine-induced permeability.
- Antineoplastic: Shikonin at 5-10 mg/kg daily fully inhibited sarcoma 180 ascites in mice and prolonged survival by 92.5% at 10 mg/kg.
- Other: Shikonin and acetylshikonin weakly analgesic and antipyretic; aqueous extract antigonadotropic and terminated early pregnancy in mice and rabbits; shikonin compounds relaxed isolated intestine.
Source: Zhu YP. Chinese Materia Medica: Chemistry, Pharmacology and Applications. Harwood Academic, 1998, p. 169.
Relationships
Full-screen graph →Click a node for details · double-click to expand it · Ctrl/⌘ + scroll or two fingers to zoom and pan.
Botanical Description
Lithospermum erythrorhizon is a perennial herb of the family Boraginaceae native to grassy hillsides and open woodland in China, Korea and Japan. From a thick, woody, deeply purple-red taproot it produces several erect, bristly-hairy stems 40-90 cm tall bearing alternate, sessile, lanceolate to ovate-lanceolate leaves 3-8 cm long with strigose hairs on both surfaces. Small white, salverform flowers about 5-6 mm across with five spreading corolla lobes and a tubular throat are borne in terminal scorpioid cymes from June to August, followed by smooth, shining grey-white ovoid nutlets. The medicinally used root, harvested in autumn, is cylindrical, twisted, 7-14 cm long and 1-2 cm thick, with deeply furrowed purple-red bark that stains the fingers due to its high content of naphthoquinone pigments (shikonin and acetylshikonin).
Active Constituents
Shikonin and its esters (acetylshikonin, isobutyrylshikonin, isovalerylshikonin, beta,beta-dimethylacrylshikonin, deoxyshikonin)
Naphthoquinone pigmentsConcentration: the red pigments of the root. Lithospermum erythrorhizon yields predominantly the R-configured shikonin series; percentage figures quoted in the literature are usually for concentrated extracts rather than for crude root, so a raw-drug percentage should not be inferred from them.
The naphthoquinone pigments are the constituents behind the drug's traditional blood-cooling, rash-venting and wound-healing uses. Shikonin has anti-inflammatory, antimicrobial and antiproliferative activity in vitro through NF-kappaB, PI3K/Akt/MAPK and NLRP3 inflammasome pathways. Its oral bioavailability is poor, which is one reason the traditional uses are largely topical. Reported toxicological effects include nephrotoxicity and skin allergy.
beta,beta-Dimethylacrylalkannin and other alkannin (S-form) esters
Naphthoquinone pigments (alkannin enantiomer series)Concentration: the dominant pigments of Arnebia euchroma, which is produced in Xinjiang and northwest China; beta,beta-dimethylacrylalkannin is used as the single marker in quantitative multi-component analysis of Zi Cao
Alkannin is the S-enantiomer of shikonin. Arnebia euchroma yields mainly S-form naphthoquinone derivatives while Lithospermum erythrorhizon yields mainly R-form ones. This is the sharpest chemical distinction between the two plants sold under the name Zi Cao, and it means pharmacological data generated on shikonin cannot simply be transferred to an Arnebia-sourced batch or vice versa.
Pyrrolizidine alkaloids (intermedine, intermedine N-oxide, echimidine, echimidine N-oxide)
1,2-unsaturated pyrrolizidine alkaloidsConcentration: total of eight measured pyrrolizidine alkaloids was 71.16-515.73 micrograms per gram across 15 batches of Lithospermum erythrorhizon and 23.35-207.13 micrograms per gram across 11 batches of Arnebia euchroma. Lycopsamine, 7-acetyllycopsamine and their N-oxides were not detected in L. erythrorhizon; 7-acetyllycopsamine and its N-oxide were not detected in A. euchroma.
Both source plants are Boraginaceae and carry 1,2-unsaturated pyrrolizidine alkaloids, which are bioactivated in the liver to pyrrolic esters that alkylate sinusoidal endothelial cells and cause hepatic sinusoidal obstruction syndrome, formerly veno-occlusive disease. In a margin-of-exposure risk assessment combining measured content with relative potency factors, individual batches of Lithospermum erythrorhizon reached medium risk when taken orally, while Arnebia euchroma was low or no risk on account of its lower content; external use of both carried no risk. Earlier phytochemical work on L. erythrorhizon had isolated three pyrrolizidine alkaloids including one new compound, hydroxymyoscorpine.
⚠ Drug Interactions
Comfrey (Symphytum), Tu San Qi (Gynura), Kuan Dong Hua (Tussilago), Senecio species and other pyrrolizidine-alkaloid-containing herbs; and hepatotoxic drugs generally
The pyrrolizidine alkaloid burden of the two Zi Cao source plants has been quantified: 71.16-515.73 micrograms per gram in Lithospermum erythrorhizon and 23.35-207.13 micrograms per gram in Arnebia euchroma. Because 1,2-unsaturated pyrrolizidine alkaloids share a single bioactivation route and a single hepatic target, exposures from different herbs in a formula sum, and a margin-of-exposure assessment placed individual L. erythrorhizon batches at medium risk on oral use even in isolation.
Clinical note: Do not stack pyrrolizidine-alkaloid-bearing herbs in one prescription. Prefer external use, where the same assessment found no risk. Avoid prolonged internal courses, and avoid internal use altogether in pregnancy, in infants, and in patients with existing liver disease.
Gonadotropin preparations (FSH and hCG), clomifene and other fertility treatments
Acetylshikonin from Zicao given by gavage to Sprague-Dawley rats for two weeks significantly reduced the pregnancy rate at 1080 mg/kg, an effect that recovered a month after withdrawal. Serum FSH and LH fell, anterior pituitary FSH secretion but not synthesis was reduced, and developing and mature follicles in the ovarian cortex were fewer; the authors attributed this to reduced expression of synaptotagmin-1 and SNAP-25, impairing gonadotropin exocytosis. Older pharmacological literature likewise describes antigonadotropic activity for Lithospermum, with inhibition of GnRH-stimulated LH release in cultured pituitary cells. The effect was seen only at the highest of three doses in rats, so its relevance to human therapeutic doses is unestablished.
Clinical note: Avoid internal Zi Cao in patients undergoing fertility treatment or actively trying to conceive. Do not present the antifertility signal as a contraceptive effect: it was dose-dependent, incomplete and reversible in rats and has never been tested in humans.
Methotrexate and other agents used in the medical management of early or ectopic pregnancy; and any medication taken during pregnancy
Shikonin from Lithospermum erythrorhizon inhibited viability of HTR-8/SVneo human trophoblast cells in a concentration- and time-dependent way and induced pyroptosis, with cell swelling, membrane pore formation, LDH release and IL-1 beta release. The effect ran through cathepsin B activating the NLRP3 inflammasome: the CTSB inhibitor CA-074 abolished it and the NLRP3 inhibitor MCC-950 blocked the downstream pyroptosis markers. The investigators were explicitly exploring shikonin as a treatment for ectopic pregnancy, which is a direct statement that the compound kills trophoblast. Evidence is in vitro only.
Clinical note: Contraindicated internally in pregnancy. This is a contraindication, not an interaction to be managed by spacing doses, and the ectopic-pregnancy research context is a reason for caution rather than a licensed indication.
Arnebia euchroma root (Xinjiang Zi Cao / Ruan Zi Cao) supplied interchangeably with Lithospermum erythrorhizon (Ying Zi Cao), and Arnebia guttata (Inner Mongolia Zi Cao)
Zi Cao is sourced from Lithospermum erythrorhizon, Arnebia euchroma and Arnebia guttata, and the batch record for this entry names two of them at once. They are not equivalent: L. erythrorhizon produces predominantly R-form shikonin esters and A. euchroma predominantly S-form alkannin esters, and measured total pyrrolizidine alkaloid content was 71.16-515.73 micrograms per gram in 15 batches of L. erythrorhizon against 23.35-207.13 micrograms per gram in 11 batches of A. euchroma, with different individual alkaloids detected in each. The risk assessment based on those figures reached different conclusions for the two plants, low or no risk for A. euchroma against medium risk for individual L. erythrorhizon batches. The classical Zi Cao of the Shen Nong Ben Cao Jing is the East Asian Lithospermum; Arnebia entered the trade later from the northwest.
Clinical note: Record the binomial, not the pinyin, on the prescription, and treat pyrrolizidine alkaloid exposure as species- and batch-dependent rather than fixed for the drug.
CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort)
1,2-unsaturated pyrrolizidine alkaloids require oxidative bioactivation, predominantly by CYP3A4, to the dehydropyrrolizidine esters that alkylate hepatic sinusoidal endothelium. Induction of that pathway would in principle increase the toxic metabolite load from a given pyrrolizidine alkaloid dose. This is class pharmacology; it has not been tested with Zi Cao.
Clinical note: Prefer external use, or omit the herb, in patients on strong CYP3A4 inducers who need a prolonged course.
Dosage
| Form | Amount | Frequency | Duration | Population | Notes |
|---|---|---|---|---|---|
| decoction | 5–10 g | Daily | — | — | 中国药典 2020 【用法与用量】5～10g。外用适量，熬膏或用植物油浸泡涂擦。 【性味与归经】甘、咸，寒。归心、肝经。 — Chinese Pharmacopoeia 2020, quoted verbatim; route and cautions preserved. Replaces a cleared category-filler value. |
Dui Yao — Herb Pairs
The classical two-herb combinations this herb appears in, each with an action neither herb has alone.
Cooling the blood and resolving toxicity is combined with nourishing and moving blood, promoting healing of burns and sores when applied topically.
External ointment for burns, eczema and non-healing sores.
Core pair of a classical formula — Zi Yun Gao, Wai Ke Zheng Zong (Chen Shigong)
Evidence Tier
Strong evidence · 5 studiesRecorded studies by study design, strongest design at the top. This is a study-design tier only, not a GRADE rating: it does not weigh risk of bias, consistency or precision.
Systematic review / meta-analysis
1
1 verified · 0 unverified
Randomized controlled trial
1
0 verified · 1 unverified
Other clinical trial
0
Observational / case report
0
In vitro / animal
3
1 verified · 2 unverified
Show 3 studies
- Pyrrolizidine alkaloids and health risk of three Boraginaceae used in TCM
- Acetylshikonin from Zicao exerts antifertility effects at high dose in rats by suppressing the secretion of GTH
- Shikonin from lithospermum erythrorhizon induces pyroptosis in trophoblast cells by activating the CTSB-NLRP3 inflammasome
Other / unclassified
0
Verified: design read from PubMed for a DOI that resolves to the cited paper Unverified: taken from the study's recorded description
Clinical Studies
Pyrrolizidine alkaloids and health risk of three Boraginaceae used in TCM
A UHPLC-MS/MS method was developed to measure eight pyrrolizidine alkaloids in the three Boraginaceae sold as Zi Cao. Total content was 71.16-515.73 micrograms per gram across 15 batches of Lithospermum erythrorhizon, 23.35-207.13 micrograms per gram across 11 batches of Arnebia euchroma, and 341.56-519.51 micrograms per gram across 11 batches of Arnebia guttata. Intermedine and its N-oxide were common to all three; lycopsamine, 7-acetyllycopsamine and their N-oxides were absent from L. erythrorhizon and 7-acetyllycopsamine and its N-oxide from A. euchroma. Risk was assessed by margin of exposure combined with relative potency: taken orally, A. euchroma and A. guttata were low or no risk while individual batches of L. erythrorhizon were medium risk; external use of all three carried no risk.
Acetylshikonin from Zicao exerts antifertility effects at high dose in rats by suppressing the secretion of GTH
Sprague-Dawley rats received acetylshikonin extract at 120, 360 or 1080 mg/kg by gavage for two weeks. Pregnancy rate fell significantly only in the 1080 mg/kg group and recovered a month after withdrawal, showing the effect to be reversible. Serum FSH and LH were significantly reduced, secretion but not synthesis of FSH was impaired in anterior pituitary cells, and developing and mature follicles were fewer in the ovarian cortex; the authors linked this to reduced synaptotagmin-1 and SNAP-25, proteins required for gonadotropin exocytosis.
Shikonin from lithospermum erythrorhizon induces pyroptosis in trophoblast cells by activating the CTSB-NLRP3 inflammasome
Shikonin inhibited HTR-8/SVneo trophoblast viability in a concentration- and time-dependent way and induced pyroptosis: cell swelling, membrane bubble and pore formation, LDH release and IL-1 beta release, with upregulation of pyroptosis-associated proteins. The cathepsin B inhibitor CA-074 abolished the effect and the NLRP3 inhibitor MCC-950 blocked downstream pyroptosis without reducing cathepsin B, placing CTSB upstream of NLRP3. The authors framed the work as a mechanistic basis for using shikonin in ectopic pregnancy, and cite the traditional description of Lithospermum erythrorhizon as an embryo-killing herb.
Comparison of the Efficacy of Topical Arnebia euchroma Product with Topical Phenytoin on Pressure Ulcer in Patients with Spinal Cord Injury: A Triple-Blind, Randomized Clinical Trial
Seventy-four patients with spinal cord injury and grade 2 or 3 pressure ulcers were randomised to Arnebia euchroma liniment or 1% phenytoin cream twice daily for five weeks. The mean reduction in Pressure Ulcer Scale for Healing score was 70.33% with Arnebia euchroma against 27.67% with phenytoin, and complete healing occurred in 16 of 37 (43.2%) versus 3 of 37 (8.1%). No adverse effects were reported in either arm. This is topical use of Arnebia euchroma, one of the two species named in this record, and does not speak to Lithospermum erythrorhizon or to internal use.
A meta-analysis of the traditional herb Zicao and its active components for atopic dermatitis
Ten animal studies covering 316 animals were pooled. Zicao treatment reduced dermatitis severity (SMD -3.30, 95% CI -4.37 to -2.23) and scratching behaviour (SMD -2.60, 95% CI -3.76 to -1.44), and reduced TNF-alpha, TSLP, IL-4, IL-13, IgE and mast cell infiltration, with no significant effect on IFN-gamma, IL-6, epidermal thickness or filaggrin expression. The authors stress that the pooled estimates are preliminary indications rather than conclusive evidence, given widespread methodological limitations. This synthesises animal models only; there is no human trial evidence, and the pooled studies used Zicao without consistently distinguishing the source species.
⚠ Safety & Contraindications
- Pregnancy
- Young children
- Liver conditions
Contraindications
Its use is cautious in patients with diarrhea due to weakness of the stomach and intestine.
Source: Xi S, Gong Y. Essentials of Chinese Materia Medica and Medical Formulas. Academic Press/Elsevier, 2017, pp. 81–84.
Historical Texts
Shen Nong Ben Cao Jing
Han dynasty, c. 200 CEReferences
- Roeder E, Rengel B. Pyrrolizidine alkaloids from Lithospermum erythrorhizon . Phytochemistry (1990) [DOI]
- Sun Q, Gong T, Liu M, Ren S, Yang H, Zeng S, Zhao H, Chen L, Ming T, Meng X, Xu H. Shikonin, a naphthalene ingredient: Therapeutic actions, pharmacokinetics, toxicology, clinical trials and pharmaceutical researches . Phytomedicine (2022) [DOI]
This information is for educational purposes only and is not intended to replace professional medical advice. Always consult a qualified healthcare provider before using any herbal remedy, especially if you are pregnant, nursing, or taking medications.
📝 Notes
Public notes from the community and your own private notes on Zi Cao.
No notes yet.