Metabolism and activation of 1,1-dimethylhydrazine and methylhydrazine, two products of N-nitrosodimethylamine reductive biotransformation.
N-Nitrosodimethylamine (NDMA) and two of its metabolites, monomethylhydrazine (MMH) and 1,1-dimethylhydrazine (UDMH) were metabolized to carbon dioxide by rat liver slices. Under these conditions, NDMA and MMH, but not UDMH, produced reactive metabolites that bound covalently to nucleic acids. Rat liver microsomes or 9000 X g supernatants were able to transform NDMA, MMH and UDMH to formaldehyde. In the case of MMH and UDMH, enzymatic and non-enzymatic pathways of formaldehyde formation were present in both liver microsomes and 9000 X g supernatants. NDMA, MMH and UDMH led to covalent binding in incubation mixtures containing either microsomes or 9000 X g supernatants. In the case of NDMA, the process was enzymatic and required NADPH in both cellular fractions. In the case of MMH, the process was enzymatic in microsomes, and required NADPH and oxygen when using UDMH or MMH and 9000 X g supernatants; interactions of a non-enzymatic nature leading to covalent binding to proteins were dominant. These results suggest that part of the carbon dioxide produced during NDMA metabolism might derive from UDMH and MMH. Similarly, a significant part of the covalent binding of NDMA metabolites to proteins in incubation mixtures containing microsomes or 9000 X g supernatants might derive from enzymatic and non-enzymatic reactions of UDMH or MMH. Also, a minor part of the covalent binding of NDMA reactive metabolites to nucleic acids might be due to further biotransformation of MMH to reactive metabolites. It may be concluded from the present results that biotransformation of NDMA to UDMH and MMH might not be a detoxication process, as previously thought, but one related to some of the toxic effects of NDMA.
D000818:Animals; D001711:Biotransformation; D002245:Carbon Dioxide / Q000378:metabolism; D004127:Dimethylhydrazines / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000378:metabolism*; D005557:Formaldehyde / Q000378:metabolism; D008297:Male; D008763:Methylhydrazines / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D004127:Dimethylhydrazines; D008763:Methylhydrazines; D002245:Carbon Dioxide; D005557:Formaldehyde; D004128:Dimethylnitrosamine