Detoxification conjugation reactions

To a great extent, conjugation produces excretable and nontoxic metabolites and thus is referred to as detoxification, but exceptions exist in each class of conjugation reaction. A more-in-depth discussion of Phase II metabolism can be found in Chapter 32. 

Many aquatic organisms have an ability to assimilate, detoxify, and depurate cyanotoxins. The process of detoxification of microcystins in fish is related to a conjugation reaction of microcystins to glutathione through the activity of glutathione S-transferase (Pflugmacher et al., 1998). The excretion of microcystins in fish and other aquatic species is mainly in bile and via feces as microcystin bound to glutathione or as a final product of the detoxification process (Sahin et al., 1996 Mohamed and Hussein, 2006). 

Fig. 5.2. Examples of herbicide detoxification reactions stimulated by the safener mefenpyr-diethyl. (A) Conjugation reaction of fenoxaprop with glutathione (GSH). (B) Oxidative demethylation of mesosulfuron-methyl.

Liver disease. The primary site of biotransformation and detoxification of DBCP is the liver. Liver dysfunctions likely to inhibit the conjugation reactions will tend to promote the toxic actions of DBCP. These precautions should be considered before exposing persons with impaired liver function to DBCP. 

Conjugation of polar groups such as amines, carboxylic acids, and phenolic hydroxyl gronps produce water-soluble compounds that are excreted and these reactions therefore fnnction as a detoxification mechanism. 

Quinones and other xenobiotics are metabolized primarily in the liver, and the end products are water-soluble compoimds that are excreted from the body. The first step in metabolism is usually an oxidative process (phase I detoxification), after which further oxidation and conjugation can occur (phase II detoxification). Although those reactions normally yield easily excreted products, some steps in the metabolic pathway may generate metabolites that are more toxic than the parent comporuid. 

A specific example involving aflatoxins is shown in Box 6.8. We shall see other examples of glutathione reacting as a nucleophile in detoxification reactions, where conjugation is not the result of nucleophilic substitution. For example, it might be nucleophilic addition to an electrophile such as an unsaturated carbonyl compound (see Box 10.20). 

Phase i reactions (interconversion reactions). Type 1 reactions introduce functional groups into inert, apolar molecules or alter functional groups that are already present. In many cases, this is what first makes it possible for foreign substances to conjugate with polar molecules via phase 11 reactions (see below). Phase 1 reactions usually reduce the biological activity or toxicity of a substance ( detoxification ). However, some substances only become biologically active as a result of the interconversion reaction (see, for example, benzo[a]pyrene, p. 256) or become more toxic after interconversion than the initial substance ( toxification ). 

Drug conjugations were once believed to represent terminal inactivation events and as such have been viewed as "true detoxification" reactions. However, this concept must be modified, because it is now known that certain conjugation... 

The Phase II enzymes play a major role in the conjugation and detoxification of nucleophiles (by sulfation or glucuronidation) and electrophiles (by reaction with... 

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