Comparative genotoxicity of 3 procarcinogens in V79 cells as related to glutathione S-transferase activity of hepatocytes from untreated rats and those fed 2% butylated hydroxyanisole.
When 7,12-dimethylbenz[a]anthracene (DMBA) and aflatoxin B1 (AFB1) were activated by hepatocytes from Fischer 344 rats fed a diet containing 2% butylated hydroxyanisole (BHA), frequencies of mutation to 6-thioguanine resistance (TGR) at the HGPRTase gene locus and to ouabain resistance (OuR) at the Na+,K(+)-ATPase gene locus in V79 cells were 30-70% less than those obtained with hepatocytes from untreated controls. A difference in the mutation frequency did not occur when dimethylnitrosamine (DMN) was activated by BHA induced- rather than control-hepatocytes. Analysis of hepatocytes from rats fed 2% BHA showed a small (1.5-fold), but significant, increase in glutathione levels over that in the controls but no change in activity of cytochrome P450. Cytosolic glutathione S-transferase (GST) activity was increased 2-3-fold in hepatocytes from rats fed the 2% BHA diet. These results suggest that mutagenic response to DMBA and AFB1 is reduced, at least in part, because of BHA-induction of hepatocyte GST activity; while activation of DMN can occur by pathway(s) unaffected by BHA-induction of these liver enzymes. In contrast to mutation frequencies, significant differences between BHA- and control-activation in the production of sister-chromatid exchange (SCE) and micronucleus formation (MN) were not detected with any of the genotoxins. It was concluded that the mechanism(s) by which SCE and MN occur are likely unrelated to the capacity of BHA to induced activity of hepatic enzymes, e.g. the GSH S-transferases, that directly or indirectly affect mutation end-points.
Rogers
C G
CG
Toxicology Research Division, Health and Welfare Canada, Ottawa.
Boyes
B G
BG
Lok
E
E
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D016604:Aflatoxin B1; D000348:Aflatoxins / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004351:Drug Resistance / Q000235:genetics; D005982:Glutathione Transferase / Q000096:biosynthesis*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D009152:Mutagenicity Tests; D051381:Rats; D011916:Rats, Inbred F344; D012854:Sister Chromatid Exchange / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
D000348:Aflatoxins; D015127:9,10-Dimethyl-1,2-benzanthracene; D016604:Aflatoxin B1; D007041:Hypoxanthine Phosphoribosyltransferase; D005982:Glutathione Transferase; D000254:Sodium-Potassium-Exchanging ATPase; D004128:Dimethylnitrosamine