Mercapturic acid formation

Reichert D, Schutz S. 1986. Mercapturic acid formation is an activation and intermediary step in the metabolism of hexachlorobutadiene. Biochem Pharmacol 35 1271-1275. 

Mercapturic acid formation in mammals is preceded by interaction with glutathione (GSH), a reaction which may be spontaneous or may be catalyzed, depending on the reactivity of the compound under investigation. The enzymes responsible for the catalysis are found in mammalian liver cytosol, however when cyanatryn was tested under appropriate conditions it neither... 

Glutathione S-Transferases (GSTs) and Mercapturic Acid Formation... 

Phase II Reactions. As with phase I reactions, phase II reactions usually depend on several enzymes with different cofactors and different prosthetic groups and, frequently, different endogenous cosubstrates. All of these many components can depend on nutritional requirements, including vitamins, minerals, amino acids, and others. Mercapturic acid formation can be cited to illustrate the principles involved. The formation of mercapturic acids starts with the formation of glutathione conjugates, reactions catalyzed by the glutathione -transferases. 

Golenhofen N et al (1995) Mercapturic acid formation in cultured opossum kidney cells. Ren Physiol Biochem 18(4) 191-197... 

The preMAP metabolites from naphthalene were extensively reabsorbed ( 24X) to be excreted with the urine as the premercapturlc acid. The lack of enterohepatlc circulation of intact MAP metabolites of the acetanilide is attributed to microfloral catabolism and not to an inability of these MAP metabolites to be translocated to the tissues (10), because MAP metabolites of the acetanilide were extensively absorbed ( 60%) from the gastrointestinal tracts of germfree and antibiotic treated rats and were excreted unchanged (except for mercapturic acid formation and sulfoxidation) in the urine or bile. Similar studies with naphthalene preMAP metabolites in control rats showed that 70 to 80X of the doses (oral) were absorbed and excreted in the urine mainly as the premercapturlc acid ( 60%) with about 17% as microfloral catabolites (11). When... 

H5. Habig, W. H., Pabst, M. T., and Jakoby, W. B., Glutathione S-transferases The first enzymatic step in mercapturic acid formation. J. Biol. Chem. 249, 7130-7139 (1974). 

Mercapturic acid formation from glutathione conjugation... 

Fig. 5.8. Giutathione-S-transferase and its role in mercapturic acid formation.

It is unclear if the transpeptidation activity represents a way for glutathione to serve as a synthetic y-glutamyl donor or is simply an insignificant transferase activity typical of many hydrolases. This enzyme probably also participates in mercapturic acid formation, and this can be viewed as a variation of the direct hydrolysis reaction in which a substituted glutathione is substrate. 

In humans mercapturic acid formation appears less significant than detoxification pathways involving glucuronide or sulphate ester formation, but is of considerable importance in other species. Halobenzenes which can cause liver damage lead to mercapturic acid formation in the rat, while non-toxic compounds such as /Mlibromobenzene do not. Such facts strongly support the idea that this pathway has a detoxification role. 

Mercapturic acid formation has been shown to occur in a variety of mammals, birds, reptiles, amphibians and fish. Insects also form glutathione conjugates but do not N-acylate the eventual S-substituted cysteine derivatives to any great extent. It is also possible that the S-carboxyalkylcysteines of plants have a similar genesis. Mercapturic acid formation is certainly one of the best studied and documented protective functions for glutathione. 

Certain metabolic reactions of cysteine do not seem to fit into any known metabolic pathway, e.g., the formation of 2-iminothiazolidine-4-carboxylic acid in rats injected with NaCN (66), or the reaction of formaldehyde with cysteine to form thiazolidine-4-carboxylic acid, which is subsequently dehydrogenated to thiazoline-4-carboxylate (66). Mer-capturic acids also belong to this group. The study of the enzymic synthesis of mercapturic acids deserves more attention since this process is rather general in many species. The fundamental reaction in mercapturic acid formation is the conjugation of a variety of substances with the S atom of Af-acetylcysteine. 

Mercapturic acid formation from lindane in rats (N. Kurihara, K. Tanaka, and M. Nakajima). 

The first investigators noted the concurrent excretion of phenols, phenol sulfatc.s, polyhydroxybcnzcncs and their glucuronidcs when mercapturic acid formation was induced in dogs by the oral administration of aromatic hydrocarbons or their monohalogen derivatives. Subsequent work demonstrated that a variety of species form mercapturic acids. Principally mammals have been studied but also some birds and insects. Recent review s on mercapturic acids include those of Williams (1959), Boyland (1962), Maw (I960), and Parke (1968). 

The observation that naphthalene feeding produced cataracts in rabbits suggested a relationship between mercapturic acid formation and sulfur amino acid metabolism in mammals, In the period between World Wars I and II, most advances in the biochemistrj of mei capturic acids were made through study of tlie nutritional effects produced by mercapturic acid precursors. During this period, the concept of mercapturic acids as... 

The primary reaction of mercapturic acid formation involves substitution of a hydrocarbon for a hydrogen on the sulfhydryl of a cysteine... 

Bray et al. (1957b) have summarized the metabolism of 19 mono-chloronitrobenzenes and related the lability of the displaced group in base hydrolysis to mercapturic acid formation. Thus, o and p-chloro-nitrobenzene produce small amounts of mercapturic acid by elimination of the chlorine the m-ch oronitrobenzene is not appreciably hydrolyzed and forms no mercapturic acid. Correspondingly, the ortho and para fluoro-, bromo-, and iodoiiitrobenzenes form considerable amounts of mercapturic acids (over 30% of the administered dose with fluoro- and o-bromo compounds) but the meta isomers formed none that could be isolated (Bray et al., 1953a). 

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