Biotransformation pathways, reaction

Biotransformation pathways of nitroaromatic compounds are believed to result from nitroreductases that have the ability to use nitro as either one- or two-electron acceptors. One-electron acceptance by the nitro compounds results in the production of the nitro radical-anion. This nitro radical-anion becomes one of the most aggressive species in biological systems because of its reaction on endogenous molecules (DNA bases) and its well-known catalytic ability to transfer one electron to molecular oxygen with superoxide anion formation. 

Metabolism includes all of the chemical transformations that occur in living systems. A detailed discussion of metabolism is beyond the scope of this chapter and the reader is directed to other comprehensive resources (22). The lesson to impart to all students interested in green chemical design is that fundamental chemical reactions are the foundation of all of biotransformation. Addition reactions, conjugation reactions, substitutions and eliminations occur to chemicals found naturally inside living systems (biochemistry) and to those that are found external to living systems (xenobiotics) as well as in laboratory round-bottom flasks. Table III lists some of the more common biotransformation pathways. 

Microsomal oxidative reactions constitute the most prominent phase I biotransformation pathway for a wide variety of structurally unrelated drugs (Table 1.4). Some drugs (e.g. amphetamine, diazepam, propranolol, lignocaine) simultaneously undergo more than one type of microsomal-mediated oxidative reaction. Microsomal enzymes are located primarily in liver cells, where they are associated with the smooth-surface (without ribosomes) endoplasmic reticulum (Fouts, 1961). Lipid solubility is a prerequisite for drug access to the... 

The general biotransformation pathways for TNT, RDX, and a few other explosives are reasonably well established. However, the kinetics of the intermediate steps and overall reactions are poorly known. Application of first-order transformation kinetics in the simulation of explosive transformation in groundwater contaminant transport studies should be considered a preliminary estimate and without justification beyond observation matching. 

Two general biotransformation pathways have been observed for nitroaromatics, including TNT (1) sequential nitro-to-amino reduction, and (2) elimination of the nitro group to form nitrite. By far, the most commonly reported reactions involve the nitro-to-amino reduction in which the nitro groups are utilized as electron acceptors or cometabolites. 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

A schematic representation of the possible molecular fate and effects of organic xenobiotics taken up into animals is given in Fig. 1. It shows the relationship between the biotransformation pathways involved in the detoxication and removal of xenobiotics and those involved in the generation of toxic molecular species. It identifies four potential sources of toxic molecular species derived either directly or indirectly from the presence of the organic xenobiotic, viz. the parent compound itself, reactive metabolites and free radical derivatives of the compound, and enhanced production of toxic oxygen species (oxyradicals). The scheme and the details of the reactions and enzymes involved (Table 1-3) are based largely on mammalian and other vertebrate studies. 

Scheme 3.9 Designed biotransformation pathway starting from oleic acid yielding either n-nonanoic acid and oa-hydroxynonanoic acid or n-octanol and 1,10-decanedioic acid by multistep enzyme-catalyzed reactions.

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