Inhibition of xenobiotic-induced genotoxicity in cultured precision-cut human and rat liver slices

In this study precision-cut liver slices have been used to evaluate the eff ects of the flavone tangeretin, the flavonoid glycoside naringin and the fl avanone naringenin (the aglycone derived from naringin) on xenobiotic-induc ed genotoxicity. Liver slices were cultured for 24 h in medium containing [ H-3]thymidine and the test compounds and then processed for autoradiographi c determination of unscheduled DNA synthesis (UDS). The cooked food mutagen 2-amino-1-methyyl-6-phenylimidazo[4,5-b]pyridine (PhIP) markedly induced U DS in cultured human liver slices and both 2-acetylaminofluorene (2-AAF) an d aflatoxin B-1 (AFB(1)) induced UDS in cultured rat liver slices. Tangeret in (20 and 50 mu M) was found to be a potent inhibitor of 5 and 50 mu M PhI P-induced UDS in human liver slices, whereas 20 and 50 mu M naringenin was ineffective and naringin only inhibited genotoxicity at a concentration of 1000 mu M. In rat liver slices 50 mu M tangeretin inhibited 10 and 50 mu M 2-AAF-induced UDS, whereas 50 mu M naringenin and 100 and 1000 mu M naringi n were ineffective. None of the three flavonoids examined inhibited 5 mu M AFB(1)-induced UDS in rat liver slices. The inhibition of PhIP- and 2-AAF-i nduced UDS by tangeretin is probably attributable to the inhibition of the human and rat cytochrome P-450 isoforms which are responsible for the bioac tivation of these two genotoxins. Although flavonoids can modulate xenobiot ic-induced genotoxicity in human and rat liver slices, any protective effec t is dependent on the particular combination of genotoxin and flavonoid exa mined. These results demonstrate that cultured precision-cut liver slices m ay be utilised as an in vitro model system to examine the modulation of xen obiotic-induced genotoxicity by flavonoids and other dietary components. (C ) 1999 Elsevier Science B.V. AU rights reserved.