Acyl glucuronides hydrolysis

Acyl glucuronides (i.e., ester glucuronides of general structure 11.6) are formed as conjugates of carboxylic acids. These compounds are rather uniquely reactive a) they are far more sensitive to chemical hydrolysis than ether... 

Fig. 11.1. Regio-isomerization of acyl glucuronides. Migration of the /3-1-acyl group from C(l) to C(2) by intramolecular nucleophilic attack. Migration can continue to C(3) and then C(4). Such reactions are usually competitive with chemical hydrolysis [25][26],... 

A quite comprehensive study was reported on the enzymatic hydrolysis of zenarestat acyl glucuronide [31]. The major metabolite of the aldose reductase inhibitor zenarestat (11.8) in humans and rats is the acyl glucuronide. This compound was unstable at physiological pH, being converted to its positional isomers and to the aglycone with a global tl/2 value of 25 min at pH 7.4 and 37°. In both rat and human blood, hydrolysis was accelerated by the... 

F. M. Brunelle, P. K. Verbeeck, Conjugation-Deconjugation Cycling of Diflunisal via Beta-Glucuronidase Catalyzed Hydrolysis of Its Acyl Glucuronide in the Rat , Life Sci. 

The metabolism of benzyl acetate involves very rapid hydrolysis to acetate and benzyl alcohol. The latter is subsequently mainly oxidized to benzaldehyde and benzoic acid. A small part of the benzyl alcohol may be conjugated with sulfate, leading, ultimately, to fonnation of a glutathione conjugate that is excreted as mercapturate in urine. The benzoic acid is excreted mainly as hippurate and, to a lesser extent, as acyl glucuronide (see Figure 1). 

Glucuronidation of carboxylic acids results in unstable acyl glucur-onides, which are prone to hydrolysis, isomerization and covalent binding to proteins and amino adds. Isomerization refers to translocation of the acyl group to the 2-, 3- and 4-positions of the GA molecule. These isomers can transiently undergo chain opening, which exposes reactive aldehydes to cellular nucleophiles [37]. 

Hydrolysis of /3-glucuronides (I r = alkyl, aryl, or acyl) by the enzyme from mammalian or non-mammalian sources is powerfully and competi-... 

As with acetolysis, the perfluoroacyl anhydrides too can be used for simultaneous hydrolysis and acylation. Thus, ether glucuronides, after methylation with methanolic diazomethane on the milligram scale, can be acylated by treatment of the dried residue with, e.g., PFPA (100 pi) in ethyl acetate (20 pi) at 65 °C for one hour. The mixture is evaporated to dryness with nitrogen and the residue is dissolved in ethyl acetate for analysis by GC [111]. 

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