Effect of quercetin on the genotoxic potential of cisplatin.
The natural product flavonoid quercetin has been shown to sensitise cells to the cytotoxic potential of cisplatin. Both cisplatin and quercetin are genotoxicants. As quercetin is currently in clinical trial as a cytotoxicant-sensitising agent, we wanted to elucidate whether it affects the genotoxicity associated with cisplatin. The genotoxic potential of both agents alone and in combination was studied in Salmonella typhimurium strains TA 98, TA 100 and TA 102 and by assessment of unscheduled DNA synthesis (UDS) in rat hepatocytes. Furthermore, effects of quercetin on levels of cisplatin-DNA adducts were studied in hepatocytes by ELISA. Cisplatin was mutagenic in all 3 bacterial strains and quercetin in strain TA 98. The number of revertant Salmonella colonies observed with the combination did not differ significantly from that caused by the drugs on their own. In the UDS assay, cisplatin was genotoxic but quercetin was not. In combination, quercetin decreased the nuclear grain count caused by cisplatin, but quercetin did not alter the level of cisplatin-DNA adduct formation in hepatocytes. Our results suggest that the mutagenic potential of the combination cisplatin-quercetin, as judged by the bacterial short-term test, does not exceed that associated with the individual components. However, in hepatocytes, quercetin appears to inhibit repair of cisplatin-induced DNA damage. Therefore, in patients who are to be treated with a combination of cisplatin and quercetin, the risk of genotoxicity in normal tissues will have to be taken into consideration.
Cross
H J
HJ
Medical Research Council Toxicology Unit, University of Leicester, UK.
Tilby
M
M
Chipman
J K
JK
Ferry
D R
DR
Gescher
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D002945:Cisplatin / Q000032:analysis / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009153:Mutagens / Q000633:toxicity*; D011794:Quercetin / Q000633:toxicity*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009153:Mutagens; C057270:cisplatin-DNA adduct; D004247:DNA; D011794:Quercetin; D002945:Cisplatin; D013936:Thymidine