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.