Hepatic enzymes mutagenicity

Stott, W.T. and Sinnhuber, R.O. Trout hepatic enzyme activation of aflatoxin-B] in a mutagen assay system and inhibitory effects of PCBs. Bull. Environ. Contam. Toxicol. (1978) 19, 35. 

Unlike EH and GTr activities, the production of AFL from AFB by trout hepatic enzymes was observed to increase in fish fed the higher casein diets (Table III). AFL has been shown to be carcinogenic (30) and mutagenic (53) and may be oxidized back to AFB by trout hepatic enzymes (54). It has been suggested that AFL represents a reserve pool of toxin in vivo (35, 55) and that its production is indicative of a sensitive animal species (56, 57). If AFL does indeed represent a reserve pool of AFB in trout, then its increased production by fish fed high levels of casein may predispose these particular animals to the induction of cancer. 

Nitroalkanes are acidic compounds the dissociation of a proton from a nitroalkane produces the nitroalkane anion, or nitronate, whose chemical and physical properties differ from those of the parent nitroalkane. The nitronate form of 2-nitropropane is more mutagenic in S. typhimurium TAIOO and TA 102 than is the neutral parent compound (Fiala et al., 1987b Dayal et al., 1989 Kohl et al., 1994), suggesting that propane 2-nitronate may act as an intennediate in the mechanism by w hich 2-nitropropane exerts its genotoxic and carcinogenic effects. This hypothesis is supported by studies indicating that both bacterial mutagenicity and induction of unscheduled DNA synthesis in rat hepatocytes are decreased by conditions (low pH or deuteration of the secondary carbon atom) that limit formation of the nitronate tautomer, and that the tautomerization of 2-nitropropane can be influenced by hepatic enzymes (Kohl et al., 1994). 

In summary, DMH and AOM failed to increase in vitro mutagenic frequency with or without liver extracts. However, MAM caused a dose-dependent increase in reversion frequency without hepatic enzymes as expected since MAM decomposes heterolytically to methyl-diazonium and formaldehyde (32). Methyldiazonium ions yield nitrogen and methylcarbonium, a powerful alkylating agent. Formaldehyde is oxidized to (X. In contrast to in vitro conditions, the host-mediated assay showed that intact animals converted DMH and AOM to mutagenic products. 

The observed mutagenic responses to AFB reflect the overall effects of activation and detoxification systems on the in vitro metabolism of AFB. It appeared that the effect of high casein levels fed to trout was that a greater amount of activated AFB was produced and/or that less could be detoxified by these fish than by those fed lower casein diets. If lowered cytochrome P-450 content and AE activities in fish fed the high casein diets represented a decrease in the activation of AFB, then these effects were overcome by the observed decreases in GTr activity and/or increases in AFB conversion to AFL relative to those of trout fed lower casein diets. Alternately, the results could be explained by dietary effects upon some unknown OAFB metabolizing enzyme system in trout, upon free GSH levels in hepatic tissue, or that the levels of the cytochrome P-450 involved in AFB activation were not reflected by the observed total cytochrome P-450 levels. 

The activation of DNT has been shown to be a multistep process involving metabolism in the liver, excretion into the bile, deconjugation of metabolites and further metabolism by the intestinal flora, re-uptake (enterohepatic transport) of metabolites into liver, and finally activation and binding to cellular macromolecules in the liver [56], More recent studies [57] involving rats pretreated with coal tar creosote, which potentiates the genotoxicity of 2,6-DNT, elucidated a complex interaction that balances metabolic activation, uptake, and detoxification. The study monitored intestinal flora enzyme activities, bacterial analysis, mutagenicity of urine samples, HPLC analysis, and hepatic DNA adducts over a five-week exposure period. The location of nitroreductase activity was an... 

H. Suzuki, F. Kishida, and J. Miyamoto, Induction of hepatic drug metabolizing enzymes and mutagens-activation capacity in several animal species, J. Pesticide Sci. 2, 421-426... 

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