Ethanol- or acetone-pretreatment of mice strongly enhances the bacterial mutagenicity of dimethylnitrosamine in assays mediated by liver subcellular fraction, but not in host-mediated assays

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Abstract
The activation of dimethylnitrosamine (DMN) to a bacterial mutagen in liver subcellular fraction and in intrasanguinous host-mediated assays was studied, in particular the effect of pretreatment of the animals with ethanol or acetone. Salmonella typhimurium TA 92 was much more sensitive to DMN mutagenicity than TA 100 and TA 1535 or Escherichia coli WP2 uvrA and was used for the main part of the study. Noteworthy, in part already known, features of the in vitro activation are the relatively low pH optimum (pH 6–6.4), the non-linear dose-mutagenic response-relationship and the relatively high doses of DMN required for activation with control preparations. Pretreatment of mice with ethanol or acetone greatly reduced the minimal mutagenically effective concentration of DMN in the in vitro assay. Pretreatment with Aroclor 1254, an inducer frequently used in mutagenicity research, showed little effect when used alone, but reduced the potentiation by acetone. The results of the host-mediated assays substantially differed from those of the in vitro activation assays (a) in the relatively low dose of DMN required for mutagenicity to occur and (b) in the lack of potentiation by acetone- or ethanol-pretreatment. Acetone even led to a marginal decrease in mutagenicity. As a possible explanation for this apparent discrepancy we assume that with the in vitro system the activity of the dilute metabolizing system is limiting for the activation of DMN and induction therefore will increase the mutagenicity, whereas in vivo DMN is quantitatively metabolized in both induced and non-induced animals. The results show that caution has to be taken in the interpretation from in vitro results to the in vivo situation. In particular our in vivo experiments do not support the hypothesis that the induction by ethanol of an activating system with a low Km (which would strongly activate traces of DMN ingested with many foods) is one of the reasons for the increased risk of liver tumors in alcoholics.