Optimization of metabolic activation for four mutagens in a bacterial, fungal and two mammalian cell mutagenesis assays.
The optimum concentrations of Aroclor-induced rat liver S9 microsomal fraction for the mutagenic activity of the four standard mutagens 2-aminofluorene (2-AF), acriflavine (ACR), benzo[a]pyrene (BP) and cyclophosphamide (CP) were determined in four mutation assays. The four assays were the Ames test using Salmonella typhimurium strain TA100, cycloheximide resistance in the yeast Saccharomyces cerevisiae, the mouse lymphoma TK assay and the human peripheral lymphocyte cytogenetic assay. BP was the only mutagen to be most active at comparable S9 concentrations, of approximately 1%, for all four assays. The optimum S9 concentrations for each of the remaining three mutagens varied substantially between the four assays. ACR was a potent direct-acting mutagen in both mammalian cell assays. The mouse lymphoma TK assay results showed similar optimal values of 1.5% S9 or below for each of the four test agents. The assay with the largest variation of optimal S9 values for the four mutagens was the Ames test in strain TA100, although it also had the widest peaks of activity over the range of S9 concentrations tested. It is likely that the diversity of findings is due to a variety of metabolites affecting the different genetic endpoints that are measured in these assays. Thus from these results it is not possible for bacterial optimization data to be related to other routine in vitro systems. The use of more than one concentration of S9 would contribute useful information.
Rees
R W
RW
Beecham Pharmaceuticals Research Division, Essex, UK.
Brice
A J
AJ
Carlton
J B
JB
Gilbert
P J
PJ
Mitchell
I D
ID
D000818:Animals; D001711:Biotransformation; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D008223:Lymphoma; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects
D009153:Mutagens