Characterization of glutathione conjugates of reactive metabolites of 3'-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen

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Abstract
3''-Hydroxyacetanilide (AMAP) is a nonhepatotoxic regioisomer of acetaminophen (APAP) that nonetheless does form reactive metabolites which bind to hepatic proteins. Because differences in the nature of reactive metabolites formed from AMAP and APAP may explain differences in their propensity to cause hepatotoxicity, characterization of the reactive metabolite of AMAP was undertaken. The naturally occurring sulhydryl-containing tripeptide glutathione (GSH) was used to trap the reactive metabolites. Four mono-GSH conjugates and one di-GSH conjugate of oxidative AMAP metabolites were characterized by 1 H NMR and soft ionization (LSIMS or FAB) mass spectral techniques, as well as by comparison of liquid chromatographic and spectral chracteristics with synthetic standards. Two isomeric mono-GSH conjugates of 2-acetamidohydroquinone (2-AcHQ) are formed as well as a bis-GHS conjugate. A mono-GSH conjugate of 3'',4''-dihydroxyacetanilide (3-OH-APAP) also was formed. Thus, these GSH conjugates most likely arise by reaction of GSH with 2-acetamido-p-benzoquinone (2-APBQ) and 4-acetamidoe-o-benzoquinone (4-AOBQ), respectively, as oxidation products of the known AMAP metabolites 2-AcHQ and 3-OH-APAP. Finally, a GSH conjugate a 3''-methyoxy-''4-hydroxyacetanilide (3-OMe-APAP) was detected in bile of mice administered AMAP. This conjugate probably arises by oxidation of 3-OMe-APAP, another known metabolite of AMAP. The presumed oxidation product, N-acetyl-3-methoxy-p-benzoquinone imine (MAPQI), was synthesized and found to react with GSH to give the same GSH conjugate as that detected in bile and in incubations of 3-OMe-APA with mouse liver microsomes plus GSH. These results indicative that reactive metabolites of AMAP are similar to N-acetyl-p-benzoquinone imine (NAPQI), the major toxic metabolite of APAP, in their reactions with GSH to form arylthioether adducts.

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