Glutathione Conjugate Metabolism Mercapturic Acid Pathway

12 Glutathione Conjugate Metabolism (Mercapturic Acid Pathway) 

FIGURE 3.8 GSH conjugate metabolism formation of mercapturic acid, Ai-acetyl cysteine and thiol conjugates. 

Intermediate a-complex FIGURE 3.9 Two typical reactions catalyzed by GSTs. 

Aksoy lA, Weinshilboum RM. Human thermolabile phenol sulfotransferase gene (STM) molecular cloning and structural characterization. Biochem Biophys Res Commun 1995 208(2) 786-795. 

Anderson R, Weinshilboum R. Phenolsulfotransferase in human tissue radiochemical enzymatic assay and biochemical properties. Clin Chem Acta 1980 103 79-90. 

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Thiol methyltransferase has been detected in erythrocytes, lymphocytes, lungs, cecal, and colonic mucosae. The nature and number of thiol methyltransferases is not clear at the present time. A cytosolic enzyme and a microsomal enzyme have been reported, with the microsomal enzyme being dissociated from membrane relatively easily. The microsomal enzyme in rat liver has been purified to homogeneity. The enzyme is a 28,000-dalton monomer with an isoelectric point of 6.2. A wide variety of xenobiotic thiols are methylated, but cysteine and glutathione are not substrates. S-Methylation is an important component in the thiomethyl shunt. Thiomethyl conjugates are metabolized to the methylsulfoxides by oxidation (see Chapter 10) and reenter the mercapturic acid pathway as substrates for glutathione S-transferase. 

Figure 9. Identification of metabolites A through D in urine of rats treated with CDA led to the proposed hidden metabolites shown here in brackets. The reactive sulfate conjugate apparently undergoes glutathione conjugation, further metabolism via the mercapturic acid pathway and, finally, C-S cleavage, methylation and sulfur oxidation of C to yield D.

Figure 3 Metabolism of isothiocyanates through the mercapturic acid pathway. Isothiocyanates are conjugated with glutathione, which is promoted by glutathione S-transferase (GST). The conjugates are metabolized sequentially by y-glutamyltranspeptidase (y-GT), cystinylglycinase (CG), and N-acetyltransferase (AT) to form mercapturic acids...

Figure 2.5 Human metabolism of isothiocyanate. Initial conjugation with glutathione occurs rapidly in an epithelial cell. Subsequent metabolism via the mercapturic acid pathway lead to N-acetylcysteine conjugates that are excreted in the urine.

Humans metabolize isothiocyanates by conjugation with glutathione, and then subsequent metabolism is via the mercapturic acid pathway, and excretion, as mainly the N-acetylcysteine-isothiocyanate conjugates (Mennicke etal. 1983, 1988 Figure 2.5). The presence of N-acetylcysteine-isothiocyanate conjugates in urine provides a useful marker for isothiocyanate and glucosinolate consumption (Duncan etal. 1997 Chung etal. 1998 Sharpio et al. 1998 Rose et al. 2000). Epithionitriles are also metabolized in a similar manner (Brocker etal. 1984). 

The human metabolism of these sulphur compounds is complex and far from understood. Moreover, due to the complexity and number of potential products, it is difficult to generalize. Several compounds probably conjugate with glutathione post-absorption, and are metabolized via the mercapturic acid pathways, in a similar manner to isothiocyanates. N-acetyl-S-aUyl-L-cysteine (allylmercapturic acid), derived from diallyl disulphide, has been detected in urine from humans who have consumed garlic (de Rooji et al. 1996). The characteristic breath and perspiration odours foimd following garlic consumption are... 

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