Reductive reactions intestinal microflora

A number of functional groups, such as nitro, diazo, carbonyl, disulfide sulfoxide, alkene, and pentavalent arsenic, are susceptible to reduction, although in many cases it is difficult to tell whether the reaction proceeds enzymatically or nonenzymatically by the action of such biologic reducing agents as reduced flavins or reduced pyridine nucleotides. In some cases, such as the reduction of the double bound in cinnamic acid (C6H5CH=CHCOOH), the reaction has been attributed to the intestinal microflora. Examples of reduction reactions are shown in Figure 7.12. 

Redox reactions and hydrolysis are the predominant metabolic conversions triggered by the intestinal microflora. The primary reductive enzymes produced by the intestinal microflora are nitroreductase, deaminase, urea dehydroxylase, and azoreductase. The hydrolytic enzymes are p-glucuronidase, p-xylosidase, p-galactosidase, and ot-L-arabinosidase. Studies conducted by Macfarlane and coworkers have shown that proteolysis can also occur in the colon. More recent findings by the group indicate that bacterial fermentation of proteins in humans could account for 17% of the short-chain fatty acids in the cecum and for 38 /o in the sigmoid and the rectum. ... 

The reductive biotransformation of drugs has been one of the least studied reactions, and many of the enzymes that are involved have not been well characterized. Some of the enzymes that catalyze reductive reactions of drugs are the cytochrome P450s, molybdenum reductases, alcohol dehydrogenases, carbonyl reductases, NADPH cytochrome P450 reductase, NAD(P)H— quinone oxidoreductases, and enzymes of the intestinal microflora (Matsunaga et al., 2006 Rosemond and Walsh, 2004). 

FIGURE 5. The reduction of aromatic azo compounds to their corresponding amines is mediated by intestinal microflora. Upon absorption, these amines would be available for typical aromatic-amine metabolism. Other metabolic reactions, e.g., aromatic hydroxylation, are possible but are not illustrated in the figure. 

Bacteria within the gastrointestinal tract perform a wide variety of biochemical reactions (77). Since the lower part of the gastrointestinal tract is anaerobic, the biochemical reactions performed by intestinal microflora are usually reductive and hydrolytic in nature. Nitro-PAH metabolism by intestinal microflora has been demonstrated both in vitro and in vivo (Table 1,2). It is well established that the nitroreductases of intestinal microflora are responsible for the metabolism and bioactivation of nitro-PAHs. However, it should be noted that the intestinal microflora are not separate from the host metabolic processes and that synergistic metabolic interactions between enzymes of the gut mucosa, hepatic tissue and microflora are important in the metabolic activation of nitro-PAHs. El-Bayoumy et al. (25) and Kinouchi et al. (45) demonstrated that the predominant metabolites formed from 1-nitropyrene-treated germ-free animals (intestinal microflora were absent) were primary ring-hydroxylated derivatives of... 

Nitroreduction is the critical reaction in the bioactivation of nitro-PAHs. Germ-free and conventional animal studies indicate that intestinal microflora nitroreductases are primarily involved in enzymatic reduction of the nitro-PAHs to form arylhydroxylamines. 

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