Inter-species variation in hepatocyte activation of 2-acetylaminofluorene in salmonella mutagenicity assays with TA98 and TA98/1,8DNP(6).
In Salmonella typhimurium mutagenicity assays the metabolic activation of 2-acetylaminofluorene (2AAF) was greater by isolated hepatocytes from two species resistant to 2AAF-induced hepatocarcinogenesis, the guinea-pig and rabbit, than by hepatocytes from the highly susceptible rat liver. S. typhimurium strain TA98/1,8DNP(6) was less sensitive to 2AAF-induced mutagenesis than strain TA98. Even in the absence of bacterial esterification (TA98/1,8DNP(6)), 2AAF mutagenicity was always lowest following activation by rat hepatocytes. Paraoxon (an inhibitor of deacetylase) inhibited by more than 90% the mutagenicity of 2AAF with rat and guinea-pig hepatocytes, but only partially inhibited the mutagenicity of N-hydroxy-2-acetylaminofluorene-a metabolite of 2AAF-particularly at low substrate concentrations. In a modified mutagenicity assay in which hepatocytes and 2AAF were pre-incubated before the addition of TA98, a reduction of 2AAF mutagenicity was observed with guinea-pig but not rat hepatocytes. Thus, even when the integrity of the cells used for metabolic activation is maintained, and when bacterial esterification is avoided, conventional Salmonella assays do not show a correlation between the mutagenicity of 2AAF in vitro and its carcinogenicity in vivo. The correlation may, however, be improved by modification of in vitro conditions.
Smith
A J
AJ
School of Biochemistry, University of Birmingham, PO Box No. 363, Birmingham B15 2TT, England.
Chipman
J K
JK