Effects of cytosol on mutagenesis induced by N-nitrosodimethylamine, N-nitrosomethylurea and alpha-acetoxy-N-nitrosodimethylamine in different strains of Salmonella: evidence for different ultimate mutagens from N-nitrosodimethylamine.
N-Nitrosodimethylamine (NDMA), but not N-nitroso-N-methylurea (MNU) was more mutagenic in the Salmonella hisG428 strain, TA104, than in the hisG46 strain, TA100 in the presence of rat or hamster liver S-9 mix. As both NMDA and MNU can give rise to methyldiazonium ion (MDI) it appears that NDMA can be metabolized to an additional mutagen with a higher activity in TA104. The effects of UV and error-prone repair on NDMA and MNU-induced mutagenesis in TA104 were also different. alpha-Acetoxy-NDMA, which gives rise to the NDMA metabolite, alpha-hydroxy-NDMA, was more mutagenic in TA104 than TA100, under certain conditions. Several metabolites of NDMA (formaldehyde, 1,1-dimethylhydrazine and nitrite) were not significantly mutagenic at the concentrations that could have been generated from NDMA. It was previously reported that the microsomal-mediated mutagenesis induced by NDMA is greatly increased by cytosol in TA104, but not in TA100. The current study found that when cytosol was separated into a high and a low mol. wt fraction, neither greatly enhanced microsomal-mediated mutagenesis by NDMA in TA104. Addition of NAD to the high, but not the low mol. wt fraction resulted in greatly enhanced activation of NDMA to a mutagen in TA104. The enhancement by cytosol of NDMA-induced mutagenesis in hisG428 was only observed when both microsomes and cytosol were simultaneously present. These observations indicate that (i) the precursor to the ultimate mutagen is relatively short-lived; and (ii) the metabolism of alpha-hydroxy-NDMA to a secondary mutagenic metabolite, possibly N-nitroso-N-methylformamide, by alcohol dehydrogenase may be responsible for the ultimate mutagen with relatively high activity in TA104.
Guttenplan
J B
JB
Division of Basic Sciences, New York University Dental School, NY 10010.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D008770:Methylnitrosourea / Q000633:toxicity*; D008862:Microsomes, Liver / Q000378:metabolism; D016296:Mutagenesis; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013045:Species Specificity
D002273:Carcinogens; C014659:methyl(acetoxymethyl)nitrosamine; D008770:Methylnitrosourea; D004128:Dimethylnitrosamine