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Factors responsible for the metabolic formation and inactivation of bacterial mutagens from trans-4-acetylaminostilbene

1980; Elsevier BV; Volume: 73; Issue: 2 Linguagem: Inglês

10.1016/0027-5107(80)90191-8

1873-135X

Hansruedi Glatt, Franz Oesch, H.‐G. Neumann,

Coenzyme Q10 studies and effects

Abstract • The mutagenicity of trans -4-acetylaminostilbene (AAS) to Salmonella typhimurium TA98 was studied by testing various metabolites and related compounds and by comparison of the mutagenicity in the presence of various subcellular fractions, cofactors and enzyme inhibitors. • In the absence of a mammalian metabolizing system, only trans -4-nitrostilbene (NOS) was strongly mutagenic. trans - N -acetylaminostilbene (N-acetoxy-AAS) was about 30 times less active. trans -4-Aminostilbene (AS), trans - N -hydroxy-4-acetylaminostilbene (N-hydroxy-AAS), 4-nitrosobibenzyl and N -acetoxy-4-acetylaminobibenzyl showed mutagenic activities several hudredfold lower than that of NOS. AAS and trans -4-azoxystilbene were completely inactive. The latter compound was also not mutagenic in the presence of a mammalian metabolizing system. But AS, AAS, N-acetoxy-AAS and N-hydroxy-AAS were activated to more mutagenic products by mouse-liver post-mitochondrial fraction and an NADPH-generating system. N -Acetoxy-4-acetylaminobibenzyl was activated, but to a much weaker mutagen that the stilbene analog. • For the activation of AAS, both the microsomal fraction and an NADPH-generating system were necessary. The cytosolic fraction potentiated the mutagenicity. Paraoxon, an inhibitor of deacetylases, reduced the mutagenicity almost to zero. AS had activation requirements similar to those for AAS, with the exception that paraoxon did not show any effect upon the mutagenicity. Complementary requirements were found with N-hydroxy-AAS and N-acetoxy-AAS. The activation was prevented by the presence of paraoxon and did not absolutely require the microsomal fractions or NADPH. The microsomal and the cytosolic fractions alone were both able to activate these 2 compounds. The activation by microsomes was slightly, and that by the cytosolic fraction was strongly, potentiated by the presence of an NADPH-generating system. A closer examination with N-acetoxy-AAS surprisingly showed that NADP + or NADPH, but not NAD + or NADH, potentiated the cytosolic activation. • A variety of modifications of the metabolizing system showed similar effects on the mutagenicity of all 5 stronly mutagenic compounds, AS, AAS, N-acetoxy-AAS, N-hydroxy-AAS and NOS. Inhibition of epoxide hydratase had no effect. Thus, although it is known that epoxides are formed metabolically, they are unlikely candidates for the mutagenic species. This holds for hydroxamix acid esters too. UDP glucuronic acid or a PAPS-generating system never increased, and mostly decreased, the mutagenicity. Glutathione, but not cysteine, reduced the mutagenicity. The effects of glutathione were quantitatively similar with the various compounds tested. In contrast, the effects of UDP glucuronic acid and of the PAPS-generating system differed with different substrates. The most likely explanation is that they sequester precursors of the ultimate mutagen, whereas glutathione may directly react with a more proximate or the ultimate mutagen. • Ascorbate, which according to the literature increases the mutagenicity of N -hydroxy-2-acetylaminofluorene, potentiated the mutagenicity of all 5 AS compounds. Thus it probably operates on a relatively late step. • In conclusion, N -oxidation and N -deacetylation were essential steps in the activation, whereas conjugation reactions represented inactivation pathways in this system. The effect of ascorbate, which produces one-electron oxidation-reduction reactions, and the stimulation of the cytosolic activation of N-acetoxy-AAS by both reduced and oxidized NADP (H) invite the speculation that the ultimate mutagen might be formed either by a one-electron oxidation of the aryl hydroxylamine or by a one-electron reduction of the arylnitroso compound.