Mercapturic acid mechanism

Glutathione and sulfatation conjugations are important pathways for generally detoxifying endogenous substrates and xenobiotics (Commanndeur et al. 1995). However, some produced metabolites (ie mercapturic acids, O-sulfo conjugates) are toxic by different mechanisms, often by reaction with DNA and other cellular nucleophiles. 

FIGURE 37.2. Metabolism and mechanism of acetaminophen toxicity. Bioactivation of acetaminophen by P450 enzymes results in the formation of the reactive intermediate (NAPQI) which forms covalent protein adducts with glutathione which is then converted to mercapturic acid. When the amount of the reactive metabolite formed exceeds the glutathione available for binding, the excess metabolite binds to tissue molecules resulting in centrilobular hepatic necrosis. 

The mercapturic acid pathway appears to have evolved as a protective mechanism against xenobiotic-induoed hepatotoxicity or... 

For purposes of discussion, the mercapturic acid precursors are classified according to the mechanism of conjugation with glutathione. The conjugation is catalyzed by an enzyme which Ls specific for each type. 

The production of an epoxide intermediate provides a mechanism for tlie formation of premercapturic acids. These conjugates are true metabolic products of aromatic hj droearbons, the mercapturic acids being artifacts produced in the isolation procedures. 

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