Nitroreduction

Benznidazole, a nitroimidazole derivative, has a mode of action that seems to involve covalent modification of macromolecules by nitroreduction intermediates. 

Nitro polycyclic aromatic hydrocarbons are environmental contaminants which have been detected in airborne particulates, coal fly ash, diesel emission and carbon black photocopier toners. These compounds are metabolized Tn vitro to genotoxic agents through ring oxidation and/or nitroreduction. The details of these metabolic pathways are considered using 4-nitrobiphenyl, 1- and 2-nitronaphthalene, 5-nitro-acenaphthene, 7-nitrobenz[a]anthracene, 6-nitro-chrysene, 1-nitropyrene, 1,3-, 1,6- and 1,8-dinitro-pyrene, and 1-, 3- and 6-nitrobenzo[a] pyrene as examples ... 

Saito et al. (134) found that the cytosolic nitroreductase activity was due to DT-diaphorase, aldehyde oxidase, xanthine oxidase plus other unidentified nitroreductases. As anticipated, the microsomal reduction of 1-nitropyrene was inhibited by 0 and stimulated by FMN which was attributed to this cofactor acting as an electron shuttle between NADPH-cytochrome P-450 reductase and cytochrome P-450. Carbon monoxide and type II cytochrome P-450 inhibitors decreased the rate of nitroreduction which was consistent with the involvement of cytochrome P-450. Induction of cytochromes P-450 increased rates of 1-aminopyrene formation and nitroreduction was demonstrated in a reconstituted cytochrome P-450 system, with isozyme P-448-IId catalyzing the reduction most efficiently. 

Most nitroreductases found in bacteria to date fall into this type I category. Type I nitroreductive transformations may be limited by the first of two electron transfers in a tight sequence of one-electron transfers since the enzymatic rates correlate with the corresponding (ArN02) (see Eq. 14-32) values (Riefler and Smets, 2000). However, it has also been noted that the free energies of the one-electron and two-electron reductions correlate with one another, and therefore this thermodynamic data may not distinguish between the one- vs. two-electron possibilties (Nivinskas et al., 2001). 

Oral contraceptives alter the metabolism of some benzodiazepines that undergo oxidation (chlordiazepoxide, alprazolam, diazepam) or nitroreduction (nitrazepam) (334). Oral contraceptives inhibit enzyme activity and reduce the clearances of these drugs. There is nevertheless no evidence that these interactions are of clinical importance. For other benzodiazepines that undergo oxidative metabolism, such as bromazepam and clotiazepam, no change has ever been found in oral contraceptive users. 

Although studies suggest that dietary incorporation of fermentable carbohydrates increases microfloral metabolism of xenobiotics, Rowland et al. (23) reported that dietary pectin did not uniformly increase the activity of intestinal microfloral nitroreductases that is, dietary pectin increased the cecal nitroreduction of p-nitrobenzoic acid and metronidazole, but not p-nitrophenol, 2-amino-4-nitrotoluene, or 4-amino-2-nitrotoluene. The presence of intes-... 

These studies indicate 1) fermentable fiber increases the total number of viable anaerobic bacteria in the cecum, but not the stomach or small intestine of rats 2) the microfloral capacity for hydrolysis of glucuronide conjugates, for nitroreduction, and for azoreduction is elevated in fermentable fiber-fed rats 3) this increased capacity for microfloral metabolism of nitrobenzene and dinitrotoluene is correlated with an elevation in the toxicity of these nitroaromatics 4) the role fiber plays in the modulation of chemical toxicity is a function of the fiber-type and the structure of the toxicant. 

R.H. Heflich et al., DNA adduct formation and mutation induction by nitropyrenes in Salmonella and Chinese hamster ovary cells Relationships with nitroreduction and acetylation. Environ. Health Perspect. 62, 135-143 (1985)... 

TNT is readily absorbed through skin, especially when skin is moist. It is excreted in urine more than in feces some is found in bile. The major biotransformation reaction is nitroreduction and, to a lesser extent, oxidation. The main metabolite formed by nitroreduction seems to be 4-amino-2,6-dinitrotoluene (4-ADNT). Other metabolites include 2-amino-4,6-dinitrotoluene (2-ADNT), 2,4-diamino-6-nitrotoluene, and 2,6-diamino-4-nitrotoluene. The metabolites are excreted in the urine as glucuronide conjugates and in the free form. Ring oxidation products of TNT such as trinitrobenzylalcohol, trinitrobenzoic acid, and simultaneous oxidation and reduction metabolites such as 2,6-dinitro-4-amino-benzylalcohol and 2,6-dinitro-4-amino-m-cresol are of less importance. Untransformed TNT is also excreted in the urine. ADNT and TNT concentrations were found in workers in explosives factories. 4-ADNT excretion was reported to be complete within 3M days after exposure. However, another study reported detectable urine concentration of ADNT in explosives workers even after 17 days away from the workplace. 

Helminth parasites have the capacity to reductively metabolize a variety of xenobiotics. Whereas all helminth species examined are able to reduce xenobiotics containing an azo functional group (R—N=N—R ), nitroreduction is not universally present. For example, A. suum and M. expansa reduce both azobenzene and 4-nitrobenzoic acid (20), whereas H. diminuta (21) and Onchocerca gutturosa (22) metabolize only the former. Although azoreductase and nitroreductase have not been purified from helminths, they appear to be confined to the soluble cell fraction and to use NADH, rather than NADPH, as the reduced pyridine cofactor (8). An exception is the nitroreductase from... 

Role of nitroreduction in the metabolism and mode of action of nitroheterocyclic antiparasitic drugs... 

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