An important role for cytosol in the microsomal metabolism of N-nitrosodimethylamine to a mutagen: evidence for two different mutagenic metabolites.

Microsomal-mediated mutagenesis induced by N-nitrosodimethylamine (NDMA) in Salmonella TA100 at neutral pH was only slightly affected by cytosol and was similar in its threshold type dose-response curve to mutagenesis induced by direct-acting N-nitroso-N-methyl compounds. However, mutagenesis in strain TA104 was greatly enhanced by cytosol and this mutagenesis did not exhibit a threshold. In the presence of microsomes alone NDMA was more potent in TA100 than TA104, but in the presence of microsomes plus cytosol (S-9 fraction) this order was reversed at the doses tested. A possible explanation for these results is that NDMA is metabolized by microsomes to a mutagen (presumably methyldiazonium ion; MDI) that is more potent in TA100 than in TA104, but in the presence of S-9 fraction a fraction of the NDMA is metabolized by a pathway leading to a different mutagen with a different specificity. The ratio of metabolism via these pathways appears to be dependent on pH.