Relationship Between Dimethylnitrosamine Metabolism or Activation and Its Ability To Induce Liver Necrosis in Rats

Abstract

Effects were studied of different chemicals on dimethylnitrosamine (DMN) metabolism to CO₂, covalent binding (CB) of DMN metabolites to nucleic acids in liver slices, DMN demethylase (DMNase) in liver microsomes or 9,000×g supernatants, and CB to microsome or 9,000×g proteins. Chemicals tested were: cystamine (CY), 3-amino-1H,1,2,4-triazole (AT), pyrazole (Pyr), promazine (PZ), chlorpromazine (CPZ), diphenhydramine (DPH), metapyrone (MET), and promethazine (PT). Except for the preventive effects of CY, AT, and Pyr which were previously reported, effects of these chemicals on DMN-induced liver necrosis were also established. Except for MET, which enhanced DMN-induced liver necrosis, the other chemicals had no effect. With the use of liver slices derived from Sprague-Dawley rats, all these compounds, when added to incubation mixtures, inhibited transformation of DMN to CO₂ and CB to nucleic acids, but only AT, Pyr, and CY had these inhibitory effects when they were injected into animals and when liver slices were prepared afterward. DPH, CPZ, and MET enhanced intensity of the transformation of DMN to CO₂ and CB to nucleic acid. No chemical tested modified CB to microsome proteins, whereas CY, AT, and Pyr significantly decreased intensity of CB to 9,000×g supernatant proteins. The other chemicals had no significant effects. Only Pyr decreased microsome DMNase; CPZ, PT, and PZ increased the activity of DMNase; CY, AT, Pyr, and DPH inhibited DMNase activity in 9,000×g supernatants; other chemicals had no effects. Formaldehyde formation partially proceeded under an atmosphere of O₂-free N₂. A correlation between a reductive process leading to CB and DMN-induced liver injury was suggested.