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 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 [3H]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 B1 (AFB1) induced UDS in cultured rat liver slices. Tangeretin (20 and 50 microM) was found to be a potent inhibitor of 5 and 50 microM PhIP-induced UDS in human liver slices, whereas 20 and 50 microM naringenin was ineffective and naringin only inhibited genotoxicity at a concentration of 1000 microM. In rat liver slices 50 microM tangeretin inhibited 10 and 50 microM 2-AAF-induced UDS, whereas 50 microM naringenin and 100 and 1000 microM naringin were ineffective. None of the three flavonoids examined inhibited 5 microM AFB1-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.
Lake
B G
BG
BIBRA International, Woodmansterne Road, Carshalton, Surrey, SM5 4DS, UK.
Beamand
J A
JA
Tredger
J M
JM
Barton
P T
PT
Renwick
A B
AB
Price
R J
RJ
D015073:2-Acetylaminofluorene / Q000037:antagonists & inhibitors / Q000633:toxicity; D000328:Adult; D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects*; D005260:Female; D044950:Flavanones; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000633:toxicity; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D015262:Xenobiotics / Q000037:antagonists & inhibitors* / Q000633:toxicity
D002273:Carcinogens; D044950:Flavanones; D047309:Flavones; D005419:Flavonoids; D007093:Imidazoles; D015262:Xenobiotics; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D015073:2-Acetylaminofluorene; D016604:Aflatoxin B1; C005273:naringenin; C059006:tangeretin; C005274:naringin