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

The activation of dimethylnitrosamine (DMN) to a bacterial mutagenin liver subcellular fraction and in intrasanguinous host-mediatedassays was studied, in particular the effect of pretreatmentof the animals with ethanol or acetone. Salmonella typhimuriumTA 92 was much more sensitive to DMN mutagenicity than TA 100and TA 1535 or Escherichia coli WP2 uvrA and was used for themain part of the study. Noteworthy, in part already known, featuresof the in vitro activation are the relatively low pH optimum(pH 6–6.4), the non-linear dose-mutagenic response-relationshipand the relatively high doses of DMN required for activationwith control preparations. Pretreatment of mice with ethanolor acetone greatly reduced the minimal mutagenically effectiveconcentration of DMN in the in vitro assay. Pretreatment withAroclor 1254, an inducer frequently used in mutagenicity research,showed little effect when used alone, but reduced the potentiationby acetone. The results of the host-mediated assays substantiallydiffered from those of the in vitro activation assays (a) inthe relatively low dose of DMN required for mutagenicity tooccur and (b) in the lack of potentiation by acetone- or ethanol-pretreatment.Acetone even led to a marginal decrease in mutagenicity. Asa possible explanation for this apparent discrepancy we assumethat with the in vitro system the activity of the dilute metabolizingsystem is limiting for the activation of DMN and induction thereforewill increase the mutagenicity, whereas in vivo DMN is quantitativelymetabolized in both induced and non-induced animals. The resultsshow that caution has to be taken in the interpretation fromin vitro results to the in vivo situation. In particular ourin vivo experiments do not support the hypothesis that the inductionby ethanol of an activating system with a low K_m (which wouldstrongly activate traces of DMN ingested with many foods) isone of the reasons for the increased risk of liver tumors inalcoholics.