Glutathione conjugates thiol formation

Figure 9.17 There are powerful synergies between Sauvignon Blanc grapes and yeast strains in formation of the compounds responsible for tropical fruit flavours 4-mercapto-4-methylpentan-2-one (4MMP), 3-mercaptohexan-l-ol (3MH) and 3-mercaptohexyl acetate (3MHA). Odourless cysteine and glutathione conjugates are converted to aromatic thiols by carbon-sulfur-lyase enzymes. Alcohol acetyl transferase further modifies 3MH, converting it to the more potent 3MHA.

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

As already discussed in chapter 4, reactive intermediates can react with reduced GSH either by a direct chemical reaction or by a GSH transferase-mediated reaction. If excessive, these reactions can deplete the cellular GSH. Also, reactive metabolites can oxidize GSH and other thiol groups such as those in proteins and thereby cause a change in thiol status. When the rate of oxidation of GSH exceeds the capacity of GSH reductase, then oxidized glutathione (GSSG) is actively transported out of the cell and thereby lost. Thus, reduced GSH may be removed reversibly by oxidation or formation of mixed disulfides with proteins and irreversibly by conjugation or loss of the oxidized form from the cell. Thus, after exposure of cells to quinones such as menadione, which cause oxidative stress, GSH conjugates, mixed disulfides, and GSSG are formed, all of which will reduce the cellular GSH level. 

Tetrafluoroethylene is metabolized by hepatic glutathione. S -transferase and the resulting cysteine conjugate is further metabolized by renal P-lyase. This pathway results in the formation of a reactive thiol that causes kidney toxicity in rats. 

Recently, we have characterized some break-down products of the sulfate conjugate of N-hydroxy-2AAF, and the effect of glutathione and various other thiols on the process, as well as on the formation of adducts to RNA and DNA (12-13). N-Hydroxy-2AAF was not foimd iq>on break-down of the sulfate conjugate, which confirms that the break-... 

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