Substrate concentration dependency of N-nitrosodimethylamine and N-nitrosomethylbenzylamine metabolism in rat liver.

Metabolism of N-nitrosodimethylamine (NDMA), a hepatocarcinogen, and N-nitrosomethylbenzylamine (NMBeA), an esophageal carcinogen, was comparatively investigated in rat liver. When these nitrosamines (25 micromole/kg) were administered orally to rats, the clearance of NDMA from the serum and liver was faster than that of NMBeA. The metabolic decomposition of NDMA by rat isolated hepatocytes was slower than that of NMBeA at high concentration (0.5 mM). However, at low concentration (6.7 microM) the metabolic decomposition of NDMA was faster than that of NMBeA. The ratio of NDMA demethylation to NMBeA demethylation and debenzylation by hepatic microsomes also changed depending on nitrosamine concentrations (1 microM to 1 mM), and low concentration of NDMA was demethylated rapidly. These results suggest that NDMA is metabolized to a methylating agent more effectively than NMBeA in liver, when carcinogenic doses of nitrosamines are administered.