Abstract
Effects were studied of aminoacetonitrile (AAN), dibenamine (DB) diethyldithiocarbamate (DDTC) dimethylformamide (DMF), disulfiram (DS), and 2-mercapto-1-methylimidazole (MMI) on the in vitro dimethylnitrosamine (DMN) metabolism to CO2, covalent binding (CB) of DMN metabolites to nucleic acids in liver slices, DMN demethylase (DMNase) in male rat liver microsomes or 9,000 g supernatants and CB to microsome of 9,000 g supernatant proteins. Effects of those chemicals on DMN-induced rat liver necrosis were also studied, except for DS whose preventive effect was previously reported by our laboratory. All the chemicals significantly prevented DMN-induced liver necrosis, except for MMI that had no effect. All these compounds when added to incubation mixtures containing liver slices from Sprague-Dawley rats, significantly inhibited transformation of DMN to CO2 and CB to nucleic acids and when they were injected into animals and liver slices prepared afterwards, they did so except for MMI and DMF that had no effect. None of the chemicals tested except DDTC and MMI modified CB to microsome proteins whereas the CB to 9,000 g supernatant proteins was significantly decreased by all the chemicals except MMI. DMNase activity either in microsomes or 9,000 g supernatants was significantly inhibited by all the compounds except MMI.
Similar content being viewed by others
References
Appel KE, Rickart R, Schawarz M, Kung HW (1979) Influence of drugs on activation and inactivation of hepatocarcinogenic nitrosamines. Arch Toxicol [Suppl] 2: 471–477
Arcos JC, Davies DL, Brown CH, Argus MF (1977) Repressible and inducible enzymic form of dimethylnitrosamine demethylase. Z Krebsforsch 89: 181–199
Czygan P, Greim H, Garro AJ, Hutterer F, Schaffner P, Popper H, Rosenthal O, Cooper YD (1973) Microsomal metabolism of dimethylnitrosamine and the cytochrome P-450 dependency of its activation to a mutagen. Cancer Res 33: 2983–2986
D'Acosta N, Castro JA, Castro de CR, Diaz Gomez MI, Ferreyra de EC, Fenos de OM (1975) Mechanism of dimethylnitrosamine and carbon tetrachloride-induced liver necrosis: Similarities and differences. Toxicol Appl Pharmacol 32: 474–481
Diaz Gomez MI, Castro JA (1977) Spectral changes resulting from interaction of some n-alkylnitrosamines and rat liver microsomes. Experientia 33: 643–644
Fiala E, Bobotas G, Kulakis C, Wattenberg L, Weisburger J (1977) Effects of disulfiram and related compounds on the metabolism in vivo of the colon carcinogen, 1,2-dimethylhydrazine. Biochem Pharmacol 26: 1763–1768
Fiume L, Campadelli-Fiume G, Magee PN, Holsman J (1970) Cellular injury and carcinogenesis. Inhibition of metabolism of dimethylnitrosamine by aminoacetonitrile. Biochem J 120: 601–605
Gillette JR, Mitchell JR, Brodie BB (1974) Biochemical mechanisms of drug toxicity. Ann Rev Pharmacol 14: 271–288
Godoy HM, Diaz Gomez MI, Castro JA (1978) Mechanism of dimethylnitrosamine metabolism and activation in rats. J Natl Cancer Inst 61: 1285–1289
Godoy HM, Diaz Gomez MI, Castro JA (1980) Relationship between dimethylnitrosamine metabolism or activation and its ability to induce liver necrosis in rats. J Natl Cancer Inst 64: 533–538
Grilli S, Prodi G (1975) Identification of dimethylnitrosamine metabolites in vitro. Gann 66: 473–480
Heath DF (1962) The decomposition and toxicity of dialkylnitrosamines in rats. Biochem J 85: 72–91
Lai DY, Myers SC, Woo YT, Greene EJ, Friedman MA, Argus MF, Arcos JC (1979) Role of dimethylnitrosamine-demethylase in the metabolic activation of dimethylnitrosamine. Chem Biol Int 28: 107–126
Lang M, Marselos M, Törrönen R (1976) Modifications of drug metabolism by disulfiram and diethyldithiocarbamate I. Mixed-function oxygenase. Chem Biol Interact 15: 267–276
Lake BG, Phillips JC, Cottrell RC, Gangolli SD (1978) The possible involvement of a microsomal amine oxidase enzyme in hepatic dimethylnitrosamine degradation in vitro. In: Gorrod JW (ed) Biological oxidation of nitrogen. Elsevier/North Holland Biomedical Press, New York, pp 131–135
Lake BG, Phillips JC, Heading CE, Gangolli SD (1976) Studies on the in vitro metabolism of dimethylnitrosamine by rat liver. Toxicology 5: 279–309
Lotlikar PD, Baldy WJ, Dwyer EN (1975) Dimethylnitrosamine demethylation by reconstituted liver microsomal cytochrome P-450 enzyme system. Biochem J 152: 705–708
Maling HM, Highman B, Williams MA, Saul W, Butler WM, Brodie BB (1974) Reduction by pretreatment with dibenamine of hepatotoxicity induced by carbon tetrachloride, thioacetamide or dimethylnitrosamine. Toxicol Appl Pharmacol 27: 380–394
Marselos M, Lang M, Törrönen R (1976) Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. Chem Biol Int 15: 277–287
McLean AEM, Day PA (1974) The use of new methods to measure the effect of diet and inducers of microsomal enzyme synthesis on cytochrome P-450 in liver homogenates and on metabolism of dimethylnitrosamine. Biochem Pharmacol 23: 1173–1180
Mitchell JR, Nelson SD, Torgeirsson SS, McMurtry RJ, Dybing E (1976) In: Popper H, Schaffner A (eds) Progress in liver diseases, vol. V. Grune & Strathan Inc, New York, pp 259–279
Prough RA, Ziegler DM (1977) The relative participation of liver microsomal amine oxidase and cytochrome P-450 in N-demethylation reactions. Arch Biochem Biophys 180: 363–373
Riceberg L, Simon M, Van Vunakis H, Abeles R (1975) Effects of aminoacetonitrile, an amine oxidase inhibitor, on mescaline metabolism in the rabbit. Biochem Pharmacol 24: 119–125
Schmähl D, Krüger FW, Ivankovic S, Preissler P (1971) Verminderung der Toxicität von Dimethylnitrosamin bei Ratten und Mäusen nach Behandlung mit Disulfiram. Arzneimittel Forsch 21: 1560–1562
Stripp B, Greene FE, Gillette JR (1969) Disulfiram impairment of drug metabolism by rat liver microsomes. J Pharmacol Exp Ther 170: 347–354
Stripp B, Sipes G, Mailing HM, Gillette JR (1974) Dibenamine impairment of rat hepatic microsomal enzymes and its relation to hepatotoxicity induced by CCl4 and dimethylnitrosamine. Drug Metab Dispos 2: 464–468
Zemaitis MA, Greene FE (1979) In vivo and in vitro effects of thiuram disulfides and dithiocarbamate on hepatic microsomal drug metabolism in the rat. Toxicol Appl Pharmacol 48: 343–350
Ziegler DM, Mitchell CH, Jollow D (1969) The properties of a purified hepatic microsomal mixed function amine oxidase. In: Gillette JR (ed) Microsomes and drug oxidations. Academic Press, New York, pp 173–187
Author information
Authors and Affiliations
Additional information
Supported in part by Grant AM 13195-11 from the National Institute of Arthritis, Metabolism, and Digestive Diseases
Rights and permissions
About this article
Cite this article
Gomez, M.I.D., Godoy, H.M. & Castro, J.A. Further studies on dimethylnitrosamine metabolism, activation and its ability to cause liver injury. Arch Toxicol 47, 159–168 (1981). https://doi.org/10.1007/BF00368676
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00368676