STUDIES ON THE REACTIVITY OF ACYL GLUCURONIDES .7. SALICYLIC ACYL GLUCURONIDE REACTIVITY IN-VITRO AND COVALENT BINDING OF SALICYLIC-ACID TO PLASMA-PROTEIN OF HUMANS TAKING ASPIRIN

Salicyl acyl glucuronide (SAG) is a significant metabolite of salicylic acid (SA) and aspirin. We have shown that, under physiological conditions in vitro, SAG undergoes rearrangement in a manner consistent with acyl migration to its 2-, 3- and 4-O-acyl positional isomers as the predominant pathway (T1/2 values were 1.4-1.7 hr in buffer at pH 7.4 and 37 degrees). Incubation of SAG or a mixture of its rearrangement isomers (be-SAG) (each at similar to 50 mu g SA equivalents/mL) with human serum albumin (HSA, at similar to 40 mg/mL) revealed the formation of covalent adducts with the protein, with peak concentrations of 1-2 mu g SA equivalents/mL. The data support a role for the rearrangement/glycation mechanism of adduct formation. Covalent adducts of SA were also detected in the plasma of humans taking aspirin (at greater than or equal to 1200 mg/day), but the concentrations were low (much less than 100 ng SA equivalents/mL). Reactivity of SAG thus provides a mechanism (though of uncertain quantitative importance) of covalent attachment of the salicyl moiety of aspirin to tissue macromolecules, which is in addition to its well-known acetylating capacity.