Summary
The effect of an in vivo treatment with the carboxylesterase inhibitor bis-p-nitrophenylphosphate (BNPP) on the hydrolysis of 1-(N-methyl-N-nitrosamino)-methylacetate (NNMA), 1-(N-methyl-N-nitrosamino)-methylbutyrate (NNMB), 1-(N-methyl-N-nitrosamino)-methylbenzoate (NNMBz) and 1-(N-methyl-N-nitrosamino)-methylpivaloate (NMMP) in rat tissue homogenates was studied. The rates of hydrolysis were specific for each compound and different in every organ tested; the extent of inhibition of the hydrolysis by BNPP was also substrate and organ specific. In some cases no inhibition at all was observed. The rate of elimination of NNMA, NNMB, and NNMP from blood was not influenced by BNPP pretreatment. The LD50 of NNMA after i.v. application showed a rise of 85% with a BNPP pretreatment. BNPP also influenced the carcinogenicity of NNMA, whereby the total carcinogenic potency was not altered, but the organotropism had changed slightly.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- NNMA:
-
1-(N-methyl-N-nitrosamino)-methylacetate
- NNMB:
-
1-(N-methyl-N-nitrosamino)-methylbutyrate
- NNMBz:
-
1-(N-methyl-N-nitrosamino)-methylbenzoate
- NNMP:
-
1-(N-methyl-N-nitrosamino)-methylpivaloate
- BNPP:
-
bis-p-nitrophenylphosphate
- DSF:
-
disulfiram
References
Bertram B, Frei E, Scherf HR, Schumacher J, Tacchi AM, Wiessler M (1985) Influence of a prolonged treatment with disulfiram and D(-) penicillamine on nitrosodiethylamine induced biological and biochemical effects in rats. J Cancer Res Clin Oncol 109:9–15
Block W, Arndt R (1978) Chromatographic study on the specificity of bis-p-nitrophenylphosphate in vivo. Biochim Biophys Acta 524:85–93
Caesar R (1982) Zum Metabolismus von Dialkylnitrosaminen. Thesis, University of Heidelberg
Caesar R, Frank N, Wiessler M (1984) Stability of various alphaesters of 1-(N-methyl-N-nitrosamino)-methanol in vitro and in vivo. Carcinogenesis 5:1231–1234
Cavalli-Sforza L (1974) Biometrie. Fischer Verlag, Stuttgart, pp 171–173
Druckrey H, Preussmann R, Ivankovic S, Schmähl D (1967) Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitrosoverbindungen an BD-Ratten. Z Krebsforschung 69:103–201
Eid P, Goeldner MP, Hirth CG, Jost P (1981) Photosuicide inactivation of acetylcholinesterase by nitrosamine derivatives. Biochemistry 20:2251–2256
Frank N, Wiessler M (1986) Inhibition of the metabolism of N-nitrosoacetoxymethyl-methylamine in the rat by disulfiram. Carcinogenesis (in press)
Habs M, Schmähl D, Kretzer H (1981) Effect of disulfiram on acetoxymethyl-methylnitrosamine induced tumors in rats. Oncology 38:18–22
Jaerv J, Kesvatera T, Aaviksaar A (1976) Structure-activity relationships in acetylcholinesterase reactions. Eur J Biochem 67:315–322
Junge W, Krisch K (1975) The carboxylesterases/amidases of mammalian liver and their possible significance. CRC Crit Rev Toxicol 3:371–434
Peto R, Pike MC, Day NE, Gray RG, Lee PN, Parish S, Peto J, Richards S, Wahrendorf J (1980) Guidelines for simple, sensitive significance tests for carcinogenic effects in long-term animal experiments. In: IARC Monographs Suppl Vol 2, Lyon
Roller PP, Shimp DR, Keefer LK (1975) Synthesis and solvolysis of methyl(acetoxymethyl)nitrosamine. Solution chemistry of the presumed carcinogenic metabolite of dimethylnitrosamine. Tetrahedron Letters 25:2065–2068
Rosenkranz G (1982) APL-Programs for the analysis of carcinogenicity experiments. Comput Programs Biomed 15:87–92
Sidhu RS, Blair AH (1975) Human liver aldehyde dehydrogenase. J Biol Chem 250:7894–7898
Wiessler M (1974) Synthese funktioneller Nitrosamine. Angew Chemie 86:817–818
Wiessler M (1975) Chemie der Nitrosamine II. Synthese funktioneller Dimethylnitrosamine. Tetrahedron Letters 30:2575–2578
Wiessler M, Schmähl D (1976) Zur carcinogenen Wirkung von N-Nitroso-Verbindungen 5. Mitteilung: Acetoxymethyl-methyl-nitrosamin. Z Krebsforsch 85:47–49
Zemaitis MA, Greene FE (1976) Impairment of hepatic microsomal and plasma esterases of the rat by disulfiram and diethyldithiocarbamate. Biochem Pharmacol 25:453–459
Author information
Authors and Affiliations
Additional information
Dedicated to Professor Dietrich Schmähl on the occasion of his 60th birthday
Rights and permissions
About this article
Cite this article
Frank, N., Caesar, R., Scherf, H.R. et al. Influence of the carboxylesterase inhibitor bis-p-nitrophenylphosphate on the rates of hydrolysis of various α-esters of 1-(N-methyl-N-nitrosamino)-methanol in vitro and in vivo and on the acute toxicity and carcinogenicity of 1-(N-methyl-N-nitrosamino)-methylacetate. J Cancer Res Clin Oncol 111, 98–102 (1986). https://doi.org/10.1007/BF00400744
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00400744