Formation of genotoxic metabolites from anthraquinone glycosides, present in Rubia tinctorum L.
Rubia tinctorum L., a medicinal plant used for the treatment of kidney and bladder stones, contains a characteristic spectrum of 9,10-anthraquinone derivatives, which are substituted in only one of the aromatic benzo rings. The majority of the anthraquinones present in the plant itself or in plant extracts are glycosides. We investigated the metabolism of two such glycosides, alizarinprimeveroside (AlP) and lucidinprimeveroside (LuP). AlP given orally to rats was metabolized to alizarin (Al) and 1-hydroxyanthraquinone (1-HA). The reductive cleavage of AlP was also observed after treatment of this compound with rat liver enzymes (S9) and NADPH. 1-HA has been reported to induce unscheduled DNA synthesis (UDS) in primary rat hepatocytes (PRH) and intestinal and liver tumors in rats after chronic treatment. The in vitro genotoxicity of 1-HA was confirmed by our present investigations. We also observed that the glycoside AlP was active at inducing UDS in PRH, but the compound was inactive in the Salmonella/microsome assay. Oral administration of LuP to rats resulted in the excretion of lucidin and rubiadin. When LuP was treated with rat liver extract and NADPH, the compound was reduced to rubiadinprimeveroside (RuP), which was hydrolyzed to rubiadin. We have recently shown that lucidin is highly genotoxic in a battery of short-term tests. We now report that rubiadin is also highly genotoxic in Salmonella typhimurium. However, in contrast to lucidin, it requires metabolic activation. In the UDS assay in PRH, rubiadin was even more potent than lucidin and equal to the positive control DMBA. In addition, the glycoside LuP is active in the Salmonella/microsome assay as well as in the UDS assay. The present work demonstrates that the uptake of the anthraquinone glycosides AlP and LuP leads to the rodent carcinogen 1-HA, and to the highly genotoxic compounds lucidin and rubiadin. This extends our previous studies and supports our suggestion that the therapeutic use of Rubia tinctorum may involve a carcinogenic risk.
Department of Toxicology, University of Hamburg Medical School, Germany.
B
B
Blömeke
B
B
Poginsky
C
C
Schmutte
H
H
Marquardt
J
J
Westendorf
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004187:Disaccharides / Q000378:metabolism / Q000633:toxicity*; D016166:Free Radical Scavengers; D006027:Glycosides; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D009152:Mutagenicity Tests; D010946:Plants, Medicinal / Q000737:chemistry*; D051381:Rats; D011919:Rats, Inbred Strains
D000880:Anthraquinones; D004187:Disaccharides; D016166:Free Radical Scavengers; D006027:Glycosides; C064334:lucidin 3-O-beta-primveroside; C064333:ruberythric acid; C010078:alizarin; C039315:lucidin; C072500:rubiadin; C061208:1-hydroxyanthraquinone