Use of precision-cut liver slices to evaluate species differences in 2-acetylaminofluorene-induced unscheduled DNA synthesis.
Precision-cut liver slices were prepared from male Sprague-Dawley rats (pretreated with or without Aroclor 1254), male Dunkin-Hartley guinea pigs, male cynomolgus monkeys, and humans. Liver slices were cultured for 24 hr using a dynamic organ culture system in medium containing [3H]thymidine and 2-acetylaminofluorene (2-AAF), aflatoxin B1 (AFB1), or 6-aminochrysene (6-AC). The liver slices were then harvested and processed for autoradiographic evaluation of unscheduled DNA synthesis (UDS). All three genotoxins induced UDS in liver slices from untreated and Aroclor 1254-treated rats. In human liver slices 2-AAF produced a concentration-dependent induction of UDS and at the highest concentration examined 2-AAF also induced UDS in guinea pig liver slices. However, 2-AAF did not induce UDS in cynomolgus monkey liver slices, although both AFB1 and 6-AC induced UDS in liver slices from this species as well as from guinea pigs and humans. The inability of 2-AAF to induce UDS in cynomolgus monkey liver slices appears to be at least partially due to the absence of hepatic CYP1A2 in this species. Precision-cut liver slices appear to be a useful alternative to primary hepatocyte cultures for studies of xenobiotic-induced genotoxicity employing the UDS technique. As shown by this study they may also be employed to evaluate species differences in xenobiotic-induced genotoxicity.
Lake
B G
BG
BIBRA International, Carshalton, Surrey, England.
Beamand
J A
JA
Wield
P T
PT
Price
R J
RJ
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D016604:Aflatoxin B1 / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D015153:Blotting, Western; D002911:Chrysenes / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000970:Antineoplastic Agents; D002911:Chrysenes; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D016604:Aflatoxin B1; C100101:6-chrysenamine