Biotransformation reaction

The process of biotransformation usually inactivates or detoxifies, or both, the administered drugs or the ingested poisons, but other reactions may also taken place. 

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Biotransformation reactions can be classified as phase 1 and phase 11. In phase 1 reactions, dmgs are converted to product by processes of functionalization, including oxidation, reduction, dealkylation, and hydrolysis. Phase 11 or synthetic reactions involve coupling the dmg or its polar metaboHte to endogenous substrates and include methylation, acetylation, and glucuronidation (Table 1). 

In biotransformation reactions, ILs can act as tunable solvents or immobilizing agents or additives. They can also be coupled to substrates or other reagents (e.g., acylating agents in Hpase-catalyzed transesterifications [62]). Recent examples of chosen applications are presented below. 

The use of ILs as solvents for biotransformation reactions is, of course, not limited to kinetic resolutions and the use of hydrolytic enzymes. Numerous other... 

Illustrative examples of biotransformation reactions include the following, although it should be emphasized that other microorganisms may be able to degrade the substrates ... 

Evaluation of success is of primary importance. Loss of substrates is a necessary but not sufficient condition, in the light of the frequency of biotransformation reactions and the formation of terminal and possibly toxic metabolites. 

For the reasons mentioned above, the development of miniature test processes becomes increasingly important for such biotransformation reactions [84]. Micro reactors can handle small volumes and process them in a well-defined manner and have been shown to have high test throughput frequencies. Hence waste reduc-... 

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

Table 1.2 Some common enzyme-catalyzed drug biotransformation reactions...

Whole-cell biotransformations frequently showed insufficient stereoselectivities and/or undesired side reactions because of competing enzymatic activities present in the cells. These side reactions can modify the substrates and/or products. Furthermore, whole-cell biotransformations are limited due to the intrinsic need to grow biomass, which generates its own metabolites that are not related to the biotransformation reactions and, therefore, which need to be removed during the downstream process. Both the cells themselves and the unrelated metabolites produced are impurities that need to be removed after the biotransformation reaction. With isolated enzymes, there are no organism and unrelated metabolites to remove after the biotransformation processes. 

Vanillin (4-hydroxy-3-methoxybenzaldehyde) is widely used in foods, beverages, perfumes and the pharmaceuticals industries. Biotransformation of isoeugenol from essential oil to vanillin represents an economic route for the supply of vanillin, which has a limited supply due to the availability of vanilli pod plants. The conversion yield of isoeugenol to vanillin by the whole-cell biotransformation process of Bacillus fusiformis was low due to the product inhibition effect. Adding resin HD-8 to the whole-cell biotransformation eliminated the product inhibition effect, yielding 8 gL 1 of vanillin in the final reaction mixture [27]. The resin HD-8 also facilitated the separation of vanillin from the used substrate. The recovered isoeugenol can be used for the subsequent biotransformation reaction. 

One advantage of whole-cell biotransformation that has not been addressed adequately in this chapter is the ability to modify compounds with complex structure, such as natural products. Natural products are ideal substrates for biotransformation reactions since they are synthesized in a series of enzymatic reactions by the whole cells. The modification of natural products by biotransformation has been reviewed recently by Azerad [ 13] and a majority of the modifications were carried out by whole-cell biotransformations. Additional examples of modification of natural products by whole-cell biotransformations can also be found in the review article by Patel [2]. Natural products are an important source of new drugs and new drug leads [53]. The use of biotransformation, especially whole-cell biotransformation, in modification of natural products for lead optimization and generating libraries of derivatives for S AR and screening studies is important for the pharmaceutical industry. 

The liver is the dominant organ in the detoxification process. The detoxification occurs by biotransformation, in which the chemical agents are transformed by reaction into either harmless or less harmful substances. Biotransformation reactions can also occur in the blood, intestinal tract wall, skin, kidneys, and other organs. 

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

Smith and Rosazza have suggested that microbial transformation experiments could best be carried out by using a series of perhaps 10 metabolitically prodigious microorganisms as microbial models. Microorganisms for such work may be selected on the basis of considerable literature precedence for their abilities to catalyze the desired biotransformation reaction (i.e., O-dealkylation, N-dealkylation, aromatic hydroxylation, and reductions). The alkaloid substrate... 

Considerable success has been achieved in isolating plant tissue culture enzymes responsible for specific steps in the biosynthesis of a range of indole alkaloids (187-191). While the subject of biosynthesis is beyond the scope of this review, the value of such enzymes in catalyzing biotransformation reactions... 

Table IV summarizes most of the information considered in this review of alkaloid transformations and considers the alkaloids studied, the reactions observed and described, and the biocatalysts that accomplish biotransformation reaction. Only the generic names of microorganisms involved in alkaloid transformations have been given in this table, and the parentheses () contain the...

TABLE 18.5. Summary of Prominent Phase I Biotransformation Reactions... 

With the exception of two dehydrogenases, all of the steroidogenic enzymes belong to the cytochrome P-450 (abbreviated as CYP) family of enzymes. The CYP enzymes are often involved with redox or hydroxylation reactions, and are also found in the liver where they are key players in biotransformation reactions (see Section 6.4). Different members of the CYP family are therefore involved with both synthesis in adrenal and gonads and hepatic inactivation of steroid hormones. 

Hydrolysis of phthalate diesters to the respective monoesters appears to be the first and the major biotransformation reaction in all of these species, but subsequent oxidative metabolism also may occur. 

The various biotransformation reactions characterized here represent only a small fraction of the biotransformations that may occur in fish. 

Considerable interest has developed concerning the nature of the mixed function oxidase system in fish and the role that this system may play in the development of toxic responses in these animals. Studies have shown that components of the mixed function oxidase system are present in relatively high concentrations in fish liver (4, 5, 6) and that the enzyme systems in this organ are capable of many of the biotransformation reactions already described for the mammalian liver (7, 8, 9). The presence of this complement of enzymes in the livers of many fishes suggests that this organ too may be particularly sensitive to insult from sub lethal concentrations of many waterborne toxicants. For this reason, methods to evaluate liver function in fish may be particularly useful in identifying the sublethal effects of certain classes of toxicants. 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

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