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.