title: Studies on the reactivity of acyl glucuronides--VII. Salicyl acyl glucuronide reactivity in vitro and covalent binding of salicylic acid to plasma protein of humans taking aspirin.
abstract: 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 (iso-SAG) (each at approximately 50 micrograms SA equivalents/mL) with human serum albumin (HSA, at approximately 40 mg/mL) revealed the formation of covalent adducts with the protein, with peak concentrations of 1-2 micrograms 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 > or = 1200 mg/day), but the concentrations were low (<< 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.
authors.affiliation: Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
authors.forename: P V
authors.initials: PV
authors.lastname: Baker
authors.forename: A R
authors.initials: AR
authors.lastname: King
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002021:Buffers; D005965:Glucuronates / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051381:Rats; D012459:Salicylates / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D020156:Salicylic Acid; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D002021:Buffers; D005965:Glucuronates; D012459:Salicylates; D012709:Serum Albumin; C066070:salicylacyl glucuronide; D020156:Salicylic Acid; D001241:Aspirin