Aloe-emodin-induced DNA fragmentation in the mouse in vivo comet assay.
Aloe-emodin (AE) and derivatives may be present as undesired components co-extracted during extraction of plants containing anthraquinonic derivatives for preparation of diacetylrhein. AE is a well-known in vitro mutagen, but up to now it failed to induce any clear in vivo genotoxic activity in the chromosome aberration assay in rat bone marrow or the in vivo/in vitro UDS test in liver. However, the two target organs noted during rodent carcinogenicity studies with danthron and emodin, two other well-known anthraquinone derivatives, are the colon and the kidney. Therefore, the choice of the organs for testing the genotoxicity of AE, i.e. bone marrow and liver, may be considered inadequate to demonstrate a possible in vivo genotoxic activity. In this context, the in vivo mouse comet assay was performed on both isolated kidney and colon cells in order to demonstrate a possible organospecific genotoxicity after oral administration of AE. Concurrently, the Ames test and the in vitro micronucleus assay with TK6 human lymphoblastoid cells were performed in their microscale version both with S9 from Aroclor 1254-induced liver or kidney, and without S9. AE induced primary DNA damage in the liver and in the kidney as observed between 3 and 6h after two oral administrations at 500, 1000 and 2000mg/kg bw, underlining an in vivo genotoxic mechanism of action. Furthermore, AE induced a clear genotoxic activity both in the Salmonella typhimurium strains TA1537 and TA98 and in the in vitro micronucleus assay in the absence as well as in the presence of metabolic activation. As no significant variation in the genotoxic activity of AE was noted when using either liver or kidney S9-mix, it seems that no quantitatively and/or qualitatively specific renal metabolism occurs. The kidney may be a target organ of AE as it is the major route of excretion. Under such conditions the separation of AE components should take place and the residual content of undesired AE derivatives should be made as low as reasonably achievable. AE present in plant extracts should be considered as an in vivo genotoxin and this property should be taken into account in the risk assessment for human exposure.
Nesslany
Fabrice
F
Laboratoire de Toxicologie Génétique - Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille Cedex, France.
Simar-Meintières
Sophie
S
Ficheux
Hervé
H
Marzin
Daniel
D
D000818:Animals; D000880:Anthraquinones / Q000032:analysis / Q000633:toxicity*; D020552:Comet Assay; D053938:DNA Fragmentation; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009928:Organ Specificity
D000880:Anthraquinones; D009153:Mutagens; C518327:aloe emodin