Relationship between dimethylnitrosamine metabolism or activation and its ability to induce liver necrosis in rats
Godoy, H.M.; Diaz Gomez, M.I.; Castro, J.A.
Journal of the National Cancer Institute 64(3): 533-538
1980
ISSN/ISBN: 0027-8874 PMID: 6928238 Document Number: 165869
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 9000 .times. g supernatants, and CB to microsome or 9000 .times. 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 established. Except for MET, which enhanced DMN-induced liver necrosis, the other chemicals had no effect. With the use of liver slices from Sprague-Dawley rats, all these compounds inhibited transformation of DMN to CO2 and CB to nucleic acids when added to incubation mixtures, 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 9000 .times. 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 9000 .times. 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.