Microsomally-mediated denitrosation of nitrosoguanidinium compounds.
A major metabolic fate of 1-methyl-2-nitro-1-nitrosoguanidine (MNNG) and nitrosocimetidine (NC) in rodents is denitrosation to generate the unmodified, parent guanidinium compound. MNNG is a potent, locally-acting carcinogen. NC is the nitrosated derivative of cimetidine, an important clinical drug administered orally for the treatment of stomach ulcers. Contrary to expectations based on the results of various short-term in vitro tests for carcinogenic potential, NC is not a carcinogen when administered to rats or mice. Rat liver microsomal enzymes have been found to be capable of catalyzing the denitrosation of MNNG, NC and an NC analog, 1,3-dimethyl-2-cyano-1-nitrosoguanidine (CyanoDMNG) in an NADPH-dependent reaction. The denitrosated guanidinium compound generated accounts for 50-70% of the nitroso compound metabolized in a microsomal incubate; nitrite is generated with a yield which represents 40-60% of the guanidinium compound produced. The cytochrome P450 inhibitors metyrapone, n-octylamine, 1-n-hexylimidazole and ellipticine inhibit the conversion of CyanoDMNG to 1,3-dimethyl-2-cyanoguanidine (Cyano-DMG) and nitrite. Microsomal NADPH-cytochrome c reductase activity is not perturbed by this series of organic compound inhibitors. Diethyl maleate at high concentrations weakly stimulates the reaction. The rates of production of the CyanoDMNG degradation products CyanoDMG, nitrite and nitrate are markedly diminished in nitrogen-saturated and in carbon dioxide-saturated microsomal incubates. Preincubating microsomes for 1 h at 37 degrees C prior to substrate and NADPH addition has no effect on the denitrosation activity. Kinetic analysis of the conversion of CyanoDMNG to CyanoDMG indicates a Km of 1.0 mM and a Vmax of 2.7 nmol/min/mg protein. Microsomes isolated from rats pretreated with the cytochrome P450 inducers pyrazole or phenobarbital show enhanced denitrosation activity. The denitrosation capacity of hamster liver microsomes is similar to that observed for rat microsomes.
Jensen
D E
DE
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140.
Stelman
G J
GJ
Williams
A W
AW
D000632:Aminopyrine / Q000378:metabolism*; D000818:Animals; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D005557:Formaldehyde / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism; D008769:Methylnitronitrosoguanidine / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D015538:Nitrosation; D009604:Nitrosoguanidines / Q000378:metabolism*; D051381:Rats
D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D009604:Nitrosoguanidines; D000632:Aminopyrine; D008769:Methylnitronitrosoguanidine; D005557:Formaldehyde; C063049:1,3-dimethyl-2-cyanoguanidine; D009249:NADP; C019503:nitrosocimetidine; C063048:1,3-dimethyl-2-cyano-1-nitrosoguanidine; D002927:Cimetidine