Detoxication glutathione conjugation

These subsequent metabolic transformations are known to be involved in the nephrotoxicity of a number of compounds such as S-(l,2-dichlorovinyl)-L cysteine and hexachlorobu-tadiene (see chap. 7). Thus, although the initial glutathione conjugation may be a detoxication step, the final product of this phase 3 reaction may prove to be toxic. 

Metabolism of foreign compounds is not necessarily detoxication. This has already been indicated in examples and will become more apparent later in this book. This may involve activation by a phase 1 or phase 2 pathway or transport to a particular site followed by metabolism. Thus, sulphate conjugation and acetylation may be involved in the metabolic activation of /V-hydroxy aromatic amines, glutathione conjugation may be important in the nephrotoxicity of compounds, methylation in metal toxicity, glucuronidation in the carcinogenicity of /1-naphthylamine and 3, 2 -dimethyl-4-aminobiphenyl. 

Substitution reactions of xenobiotics with glutathione are the most important and contribute efficiently to detoxication. Nevertheless, in some cases such as vicinal dihaloge-nated compounds, glutathione conjugation produces monosubstituted derivatives which may cycle into a highly... 

In contrast to the enhanced reactivity and toxicity of the various glucuronide, sulfate, acetyl, and glutathione conjugates, amino acid conjugates have not proven to be toxic. It has been proposed that amino acid conjugation is a detoxication pathway tor reactive acyl CoA thioesters. 

Figure 7.22 Metabolism of bromobenzene. The bromobenzene 2,3-oxide and 3,4-oxide may undergo chemical rearrangement to the 2- and 4-bromophenol, respectively. Bromobenzene 3,4-oxide may also be conjugated with glutathione, and in its absence react with tissue proteins. An alternative detoxication pathway is hydration to the 3,4-dihydrodiol via epoxide hydrolase.

The metabolite of bromobenzene that is believed to be responsible for the hepatic necrosis is bromobenzene 3,4-oxide. This reacts with liver cell protein, which causes cell death. The reactive metabolite can be detoxified by conjugation with glutathione or be detoxified by metabolism to a dihydrodiol by epoxide hydrolase. Pretreatment of animals with the enzyme inducer 3-methylcholanthrene decreases the toxicity. This is because it increases metabolism to the 2,3-oxide. This reactive metabolite is not as toxic as the 3,4-bromobenzene oxide readily undergoing rearrangement to 2-bromophenol. 3-Methylcholanthrene also induces epoxide hydrolase and so increases detoxication. 

Levels of conjugating enzymes, such as glutathione transferases, are also known to be influenced by gender and species differences as well as by drugs and other environmental factors. All of these factors will in turn affect the detoxication process. 

Mainigi and Campbell (20) have shown that low protein diets depress hepatic glutathione levels. Since enzymatic conjugation and spontaneous reaction of certain xenobiotics with hepatic glutathione is an important detoxication step with certain compounds, this depression of glutathione levels may alter the toxicity of these compounds in animals fed low protein diets. 

Different enzymatic reactions that occur during the metabolism of chemicals have been well categorized. The biotransformation and conjugation reactions may lead to either the detoxication of the toxicant and the excretion of its metabolites, or to the activation of the toxicant into more reactive intermediates. These may, in turn, react with glutathione, or tissue proteins, or nucleic acids (e.g., RNA, DNA) and undergo different metabolic reactions. 

The conjugation of xenobiotics with glutathione (GSH) in higher plants was first demtxistrated to be a major enzymatic detoxication mechanism with the atrazine herbicide in sorghum, corn, and other atrazine resistant species (77-80) (Equation 15). Since this... 

The intracellular conjugation of xenobiotics with glutathione (GSH) results in their detoxication and adjusts their polarity to facilitate excretion from the cell (for recent reviews of GSH conjugation, see 1 and 2). Here the disposition of these GSH conjugates will be discussed. 

---