Strain differences in in vitro rat hepatocyte unscheduled DNA synthesis (UDS): effect of UV is independent of strain while increased sensitivity is apparent using Fischer-344 instead of Sprague-Dawley rats.
The unscheduled DNA synthesis (UDS) assay measures DNA repair following in vitro treatment of rat primary hepatocytes. This report compares the UDS response of primary hepatocytes from 2 widely used rat strains, the Fischer-344 (F344) and Sprague-Dawley (SD) strains. Ultraviolet (UV) light and 5 known genotoxic chemicals were evaluated in each strain in parallel experiments. The chemicals tested were 2-acetylaminofluorene (2-AAF), 4-aminobiphenyl (4-AB), benzidine, dimethylnitrosamine (DMN) and N-propyl-N'-nitro-N-nitrosoguanidine (PNNG). Four of these compounds (2-AAF, 4-AB, benzidine and DMN) require metabolic activation. Benzidine and PNNG were both negative using SD rat hepatocytes, but were weakly positive using F344 rat hepatocytes. In the first of 2 experiments, 4-AB was inconclusive in SD hepatocytes, but strongly positive in F344 cells. In the second experiment, 4-AB was positive in hepatocytes from both strains. 2-AAF was more strongly positive in F344 cells than in SD cells. DMN and UV light induced positive dose responses with little or no differences between strains. It is concluded that hepatocytes from F344 rats may be more sensitive, qualitatively and quantitatively, than hepatocytes from SD rats as indicators of UDS. This difference is not due to intrinsic differences in DNA repair mechanisms but is probably due to differences in drug-metabolizing enzymes between these strains. Thus, for routine screening, F344 rats are preferable for measurement of the in vitro UDS-inducing potential of compounds.
Harbach
P R
PR
Genetic Toxicology Research, Upjohn Company, Kalamazoo, MI 49007.
Wiser
S K
SK
Smith
A L
AL
Grzegorczyk
C R
CR
Aaron
C S
CS
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000611:Aminobiphenyl Compounds / Q000633:toxicity; D000818:Animals; D001560:Benzidines / Q000633:toxicity; D004247:DNA / Q000096:biosynthesis / Q000528:radiation effects; D004260:DNA Repair; D004128:Dimethylnitrosamine / Q000633:toxicity; D008099:Liver / Q000166:cytology*; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000031:analogs & derivatives / Q000633:toxicity; D009152:Mutagenicity Tests / Q000379:methods*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014466:Ultraviolet Rays
D000611:Aminobiphenyl Compounds; D001560:Benzidines; D008769:Methylnitronitrosoguanidine; C013659:propyl-N'-nitro-N-nitrosoguanidine; C029876:benzidine; D004247:DNA; D015073:2-Acetylaminofluorene; D004128:Dimethylnitrosamine