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 metabolites of AMAP was undertaken. The naturally occurring sulfhydryl-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 1H NMR and soft ionization (LSIMS or FAB) mass spectral techniques, as well as by comparison of liquid chromatographic and spectral characteristics with synthetic standards. Two isomeric mono-GSH conjugates of 2-acetamidohydroquinone (2-AcHQ) are formed as well as a bis-GSH 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-acetamido-o-benzoquinone (4-AOBQ), respectively, as oxidation products of the known AMAP metabolites 2-AcHQ and 3-OH-APAP. Finally, a GSH conjugate of 3'-methoxy-4'-hydroxy-acetanilide (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-APAP with mouse liver microsomes plus GSH.(ABSTRACT TRUNCATED AT 250 WORDS)
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Rashed MS,Nelson SDdoi
10.1021/tx00007a007subject
Has Abstractpub_date
1989-01-01 00:00:00pages
41-5issue
1eissn
0893-228Xissn
1520-5010journal_volume
2pub_type
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