Nitroaromatics reductive metabolism

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

Hetherington, L.H., Livingstone, D.R., and Walker, C.H. (1996). Two and one-electron dependant reductive metabolism of nitroaromatics by Mytilus edulis, Carcinus maenas and Asterias rubens. Comparative Biochemistry and Physiology 113, 231-239. 

The Sertoli cell plays a key metabolic role in the processes of germ cell development. Compounds that disrupt Sertoli cell metabolism would be expected to cause testicular toxicity. For example, 1,3-dinitro-benzene and other nitroaromatic compounds cause testicular toxicity apparently by disruption of Sertoli cell function. These compounds can undergo reductive metabolism to toxic nitroso intermediates, which may be ultimately responsible for the Sertoli cell toxicity. As indicated above, microtubules play an important role in support and transport processes. Hexanedione has been studied extensively as an agent capable of altering testicular microtubules. Other compounds that disrupt microtubule assembly and Sertoli cell function include the fungicide ben-omyl and the antiinflammatory agent colchicine, both of which prevent the assembly of testicular tubulin into microtubules. 

D. (1991) Generation of free radicals during the reductive metabolism of the nitroaromatic compound, nilutamide. 

Reductive Metabolism of Nitroaromatic and Nitropolycyclic Aromatic Hydrocarbons... 

Other bacteria. Intestinal bacteria may play a critical role in the metabolic activation of certain nitroaromatic compounds in animals (119) and several reports have appeared on the metabolism of nitro PAHs by rat and human intestinal contents and microflora (120-123). Kinouchi et al. (120) found that 1-nitropyrene was reduced to 1-aminopyrene when incubated with human feces or anaerobic bacteria. More recently, Kinouchi and Ohnishi (121) isolated four nitroreductases from one of these anaerobic bacteria (Bacteroides fragilis). Each nitroreductase was capable of converting 1-nitropyrene into 1-aminopyrene, and one form catalyzed the formation of a reactive intermediate capable of binding DNA. Howard ej al. (116) confirmed the reduction of 1-nitropyrene to 1-aminopyrene by both mixed and purified cultures of intestinal bacteria. Two additional metabolites were also detected, one of which appeared to be 1-hydroxypyrene. Recently, similar experiments have demonstrated the rapid reduction of 6-nitro-BaP to 6-amino-BaP (123). 

Most studies in the microbial metabolism of nitroaromatic compounds used aerobic microorganisms. In most cases no mineralization of nitroaromatics occurs, and only superficial modifications of the structures are reported. However, under anaerobic sulfate-reducing conditions, the nitroaromatic compounds reportedly undergo a series of reductions with the formation of amino compounds. For example, trinitrotoluene under sulfate-reducing conditions is reduced to triaminotoluene by the enzyme nitrite reductase, which is commonly found in many Desulfovibrio spp. The removal of ammonia from triaminotoluene is achieved by reductive deamination catalyzed by the enzyme reductive deaminase, with the production of ammonia and toluene. Some sulfate reducers can metabolize toluene to (X) sub 2. Similar metabolic processes could be applied to other nitroaromatic compounds like nitrobenzene, nitrobenzoic acids, nitrophenols, and aniline. Many methanogenic bacteria can reduce nitroaromatic compounds to amino compounds. 

Little is known about the enzymes of the intestinal microflora that reduce drugs and other chemicals (Matsunaga et al., 2006). However, these reductions can play an important role in the metabolism of some drugs. In particular, reductions of azo bonds and nitroaromatics are catalyzed by reductases in the intestinal microflora ... 

If, during the chemical or enzymatic reduction of the nitro group, the nitroso or hydroxylamine metabolites are produced as discrete intermediates, then numerous reactions other than continued reduction to the amine becomes possible. These new reactions include many that can occur under normal physiological conditions which has led biomedical scientists to propose that the toxic actions of nitroaromatic and arylamine compounds are mediated largely by the production of their nitroso and hydroxylamine metabolites. The same fundamental chemical reactions are likely to contribute to microbial toxicity. On the other hand, several microbes appear to have taken advantage of a major reaction available to arylhydroxylamine compounds, and to have developed enzymes to direct hydroxylamine metabolism towards a pathway that can result in mineralization. 

A notable exception to the rule of thumb that the nitrosoarene compound is favored under oxidative conditions is the observation of arylhydroxylamine rather than nitrosoarene metabolite in microsomal oxidase studies of arylamine metabolism (43). In vitro studies of N-oxidation generally contain the biological reductant NADPH, which can, by a mechanism independent of cytochrome P-450 catalysis, reduce any nitroso product back to the hydroxylamine state. Our studies on CPX-catalyzed oxidation of arylamines by H2O2 did not require a reductant such as NADPH, and thus, may better reflect the actual enzymatic or equilibrium product of oxidative reactions, including microsomal oxidations. Microsomal oxidations in which substrates such as cumene hydroperoxide are used in place of O2/NADPH should yield the nitrosoarene rather than arylhydroxylamine metabolite. In the case of 4-chloroaniline, the nitroso metabolite rather than the hydroxylamine metabolite was produced however, the major product was the nitroaromatic compound, indicative of further oxidation (55). This raises the hypothetical question as to whether... 

Figure 23. A reductive pathway for microbial nitroaromatic metabolism leading to ring cleavage.

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