Mercapturic acid pathway

Goeptar, AR, Commandeur JNM, Vanommen B, et al. 1995. Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity. Relevance of the mercapturic acid pathway. Chem. Res. Toxicol. 8 3-21. 

It was hypothesized that SFN inhibits HD ACs through its metabolities. These metabolities have structural similarities to that of known HDAC inhibitors. SFN is metabolized through the mercapturic acid pathway, which... 

Vamvakas S, Kordowich FJ, Dekant W, et al. 1988a. Mutagenicity of hexachloro-1,3-butadiene and its S-conjugates in the Ames test-role of activation by the mercapturic acid pathway in its nephrocarcinogenicity. Carcinogenesis 9 907-910. 

In this chapter we survey recent findings that describe the metabolic fate of the xenobiotic moieties of mercapturic acid pathway (MAP) metabolites that are excreted from the liver with the bile. We show that the products of the MAP undergo an enterohepatic circulation that is mediated by intestinal enzymes and/or intestinal microflora. 

Urinary metabolites of acrylonitrile include 5 -(2-cyanoethyl)mercapturic acid, N-acet T-3-carboxy-5-cyanotctrahydro-I,4-3//-thiazine and thiocyanate (Kopecky et al., 1979 Langvardt et al., 1980 Gut c/ al., 1981 Sapota, 1982). The proportion excreted as thiocyanate by rats is far higher (23% of dose) after oral dosing than after intraperitoneal, intravenous or subcutaneous administration (1-4% of dose Gut et al., 1981). Other metabolites derived from the mercapturic acid pathway include. S -carboxymethylcys-teine,. S -hydroxyethylmercapturic acid [jV-acetyl-5 -(2-hydroxyethyl)cysteine] and thiodi-glycolic acid (Muller et al., 1987). 

J. Bakke and J.-A. Gustafsson, Mercapturic acid pathway metabolites of xenobiotics generation of potentially toxic metabolites during entereohep-atic circulation, TIPS, 517-521 (1984). 

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. 

Propachlor is absorbed through the gastrointestinal tract, through intact skin, and through the respiratory system after inhalation of dust or spray mist. It is metabolized via the mercapturic acid pathway. The major fecal metabolite is a cysteine conjugate. Rats administered propachlor orally excreted 98.6% of the dose in the urine and feces within 48 h. Approximately 50% is excreted as metabolites through urine or feces within 24 h. 

The mercapturic acid pathway metabolites of menadione, the 3-glutathionyl and corresponding N-acetylcysteine conjugate (mercapturic acid) are a result of a detoxicative pathway designed to remove reactive electrophilic substrates from mammalian systems (10). The... 

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.

Klasson-Wehler E, Bergman A, Kowalski B, et al. 1987. Metabolism of 2,3,4, 6-tetrachlorobiphenyl Eormation and tissue localization of mercapturic acid pathway metabolites in mice. Xenobiotica 17 477-486. 

ANDERS, M.W. (editor) (1985) Bioactivation of Foreign Compounds (New York Academic Press). BAKKE, J. and GUSTAFSSON, J.A. (1984) Mercapturic acid pathway metabolites and xenobiotics ... 

Lamoureux and Davison (1975), investigating the metabolism of propachlor in rats, found that here too the mercapturic acid pathway plays an important role. Rats treated with -propachlor excerted 20% of the dose in the form of mercapturic acid conjugate 24 hours after treatment ... 

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

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...

Glutathione Conjugate Metabolism (Mercapturic Acid Pathway)... 

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