Metabolism and activation of 1,1-dimethylhydrazine and methylhydrazine, two products of nitrosodimethylamine reductive biotransformation, in rats.
Nitrosodimethylamine (DMN) and two of its metabolites, methylhydrazine (MH) and 1,1-dimethylhydrazine (UDMH), were metabolized to CO2 by liver slices obtained from Sprague-Dawley rats. Under the conditions used, DMN and MH produced reactive metabolites that bound covalently to nucleic acids, but UDMH did not. Rat liver microsomes or 9,000 X g supernatants were able to transform DMN, MH, and UDMH to CH2O. In the cases of MH and UDMH, enzymatic and nonenzymatic pathways of CH2O formation were observed in both liver microsomes and 9,000 X g supernatants. DMN, MH, and UDMH led to covalent binding (CB) to proteins in incubation mixtures containing either microsomes or 9,000 X g supernatants. In the case of DMN, the process was enzymatic and required NADPH in both cellular fractions. In the case of MH, the process was enzymatic in microsomes and required NADPH and O2. With UDMH or MH and 9,000 X g supernatants, nonenzymatic interactions resulting in CB to proteins dominated. All these results suggest that part of the CO2 produced during DMN metabolism might be derived from UDMH and MH. Similarly, a significant part of the CB of DMN metabolites to proteins in incubation mixtures containing microsomes or 9,000 X g supernatants might be derived from enzymatic and nonenzymatic reactions of UDMH or MH. Also, a minor part of the CB of DMN-reactive metabolites to nucleic acids might have resulted from MH's further biotransformation to reactive metabolites. Overall, biotransformation of DMN and MH might not be a detoxication process, as previously thought, but one related to some of the DMN toxic effects.
D000818:Animals; D001711:Biotransformation; D004127:Dimethylhydrazines / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000378:metabolism* / Q000633:toxicity; D008658:Inactivation, Metabolic; D008297:Male; D008763:Methylhydrazines / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009002:Monomethylhydrazine / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D004127:Dimethylhydrazines; D008763:Methylhydrazines; C013958:dimazine; D004128:Dimethylnitrosamine; D009002:Monomethylhydrazine