Variability of acetaminophen metabolism in Caucasians and Orientals

Acetaminophen (paracetamol) is extensively conjugated with glucuronic acid and sulfate prior to renal excretion. A minor metabolic route involves microsomal oxidation of acetaminophen to a hepatotoxic reactive intermediate, which subsequently undergoes glutathione (GSH) conjugation, yielding cysteine and mercapturate conjugates, both of which are excreted in the urine (Slattery et al., 1987). Data collected by de Morais et al. (1989) indicated that in comparison with normal subjects, glucuronidation of acetaminophen was impaired in subjects with Gilbert's syndrome, a genetically-based impairment of bilirubin glucuronidation. Thus, inter-subject and ethnic differences in acetaminophen disposition have pharmacogenetic and toxicological implications. This study was conceived to explore these differences. Urinary excretion of acetaminophen and its metabolites was observed in 125 Caucasian and 33 Oriental subjects. No appreciable difference was noted in the mean fraction of drug excreted as glucuronide between the two groups (51.5% in Caucasians vs 51.8% in Orientals). However, the data strongly indicated that the excretion of acetaminophen glucuronide was not normally distributed. Bimodality was apparent in both groups, with 20% of Caucasian and 33% of Oriental subjects displaying relatively extensive glucuronidation. In addition, glucuronidation displayed a strong negative correlation with sulfation (r = -0.97), suggesting the existence of a compensatory mechanism between the two metabolic pathways. The mean fractional excretions of cysteine and mercapturate conjugates did show significant differences between Caucasians and Orientals (p < 0.005). In addition, the ratio of mercapturate to total GSH-derived conjugates recovered appeared to be bimodal, indicating possible heterogeneity in the conversion of the cysteine conjugate to mercapturate via N-acetylation.