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

Abstract

In this study precision-cut liver slices have been used to evaluate the effects of the flavone tangeretin, the flavonoid glycoside naringin and the flavanone naringenin (the aglycone derived from naringin) on xenobiotic-induced genotoxicity. Liver slices were cultured for 24 h in medium containing [ 3 H ]thymidine and the test compounds and then processed for autoradiographic determination of unscheduled DNA synthesis (UDS). The cooked food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) markedly induced UDS in cultured human liver slices and both 2-acetylaminofluorene (2-AAF) and aflatoxin B 1 (AFB 1) induced UDS in cultured rat liver slices. Tangeretin (20 and 50 μM) was found to be a potent inhibitor of 5 and 50 μM PhIP-induced UDS in human liver slices, whereas 20 and 50 μM naringenin was ineffective and naringin only inhibited genotoxicity at a concentration of 1000 μM. In rat liver slices 50 μM tangeretin inhibited 10 and 50 μM 2-AAF-induced UDS, whereas 50 μM naringenin and 100 and 1000 μM naringin were ineffective. None of the three flavonoids examined inhibited 5 μM AFB 1-induced UDS in rat liver slices. The inhibition of PhIP- and 2-AAF-induced UDS by tangeretin is probably attributable to the inhibition of the human and rat cytochrome P-450 isoforms which are responsible for the bioactivation of these two genotoxins. Although flavonoids can modulate xenobiotic-induced genotoxicity in human and rat liver slices, any protective effect is dependent on the particular combination of genotoxin and flavonoid examined. These results demonstrate that cultured precision-cut liver slices may be utilised as an in vitro model system to examine the modulation of xenobiotic-induced genotoxicity by flavonoids and other dietary components.