Cytosolic activation of aromatic and heterocyclic amines. Inhibition by dicoumarol and enhancement in viral hepatitis B.
- 1 October 1994
- journal article
- Published by Environmental Health Perspectives in Environmental Health Perspectives
- Vol. 102 (suppl 6) , 69-74
- https://doi.org/10.1289/ehp.94102s669
Abstract
The aromatic amines 2-aminofluorene (2AF), 2-acetylaminofluorene, and 2-aminoanthracene, and the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and 3-amino-1-methyl-SH-pyrido[4,3-b]indole (Trp-P-2) were activated by rat liver cytosolic fractions to form mutagenic metabolites in Salmonella typhimurium strains TA98, TA98NR, and TA98/1,8-DNP6. In the case of the Trp-P-2, the cytosolic activation was even more potent than the microsomal activation, which is classically ascribed to N-hydroxylation and subsequent esterification. The cytosolic activation was a) NADPH-dependent, b) induced by pretreatment of rats with 3-methylcholanthrene and especially Aroclor 1254 but not by phenobarbital, and c) inhibited by dicoumarol. The hypothesis is that, following a preliminary oxidative step in the cytosol (pure cytosolic activation) or in microsomes via prostaglandin H synthase (mixed microsomal-cytosolic activation), an oxidized intermediate of amino compounds may serve as substrate for DT diaphorase activity and bielectronically reduced to the corresponding N-hydroxyamino derivative. Purified DT diaphorase, in the presence of either NADPH or NADH as electron donor, produced mutagenic derivatives from IQ and Trp-P-2. An NADPH-dependent activation of Trp-P-2 also occurred in the liver cytosol of woodchucks (Marmota monax), but was not inhibited by dicoumarol. As previously demonstrated with liver S-12 fractions in both humans and woodchucks, the cytosolic activation of Trp-P-2 was enhanced in animals affected by hepatitis B virus infection. This enhanced metabolism, which persisted even after appearance of primary hepatocellular carcinoma in virus carriers, is likely to be ascribed to mechanisms other than DT diaphorase induction, such as glutathione depletion.Keywords
This publication has 36 references indexed in Scilit:
- Cytosolic activation of 2-aminoanthracene: Implications in its use as diagnostic mutagen in the Ames testMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 1992
- Synthesis and mutagenic activity of nitro-imidazoarenes. A study on the mechanism of the genotoxicity of heterocydic arylamines and nitroarenesMutagenesis, 1988
- Metabolic activation of 2-amino-3-methylimidazo(4, 5-f)quinoline by hepatic preparations — contribution of the cytosolic fraction and its significance to strain differencesMutagenesis, 1986
- Mechanism of activation of proximate mutagens in Ames' tester strains: The acetyl-CoA dependent enzyme in TA98 deficient in catalyzes DNA-binding as the cause of mutagenicityBiochemical and Biophysical Research Communications, 1983
- Ultimate forms of mutagenic and carcinogenic heterocyclic amines produced by pyrolysisBiochemical and Biophysical Research Communications, 1983
- Prostaglandin endoperoxide synthetase-mediated metabolism of carcinogenic aromatic amines and their binding to DNA and proteinBiochemical and Biophysical Research Communications, 1982
- Covalent binding of N-hydroxy-Trp-P-2 to DNA by cytosolic proline-dependent systemBiochemical and Biophysical Research Communications, 1982
- Degradation of mutagens from pyrolysates of tryptophan, glutamic acid and globulin by myeloperoxidaseBiochemical and Biophysical Research Communications, 1979
- Metabolic activation of 3-amino-5H-pyrido[4,3-b]indole, a highly mutagenic principle in tryptophan pyrolysate, by rat liver enzymesChemico-Biological Interactions, 1979
- Dt diaphorase I. Purification from the soluble fraction of rat-liver cytoplasm, and propertiesBiochimica et Biophysica Acta, 1962