Dissociation of increased sulfation from sulfate replenishment and hepatoprotection in acetaminophen-poisoned mice by N-acetylcysteine stereoisomers.

N-Acetylcysteine stereoisomers were compared for their ability to alter the sulfation and hepatotoxicity of acetaminophen. The clinically used L-isomer increased urinary excretion of inorganic sulfate 2-3 fold and prevented liver injury, but failed to increase acetaminophen sulfation in mice. Conversely, the nonphysiologic D-isomer failed to increase urinary excretion of inorganic sulfate or prevent hepatotoxicity, but increased acetaminophen sulfation appreciably (by 39%). The basis of the incongruence between changes in the availability of inorganic sulfate and the sulfation of acetaminophen is not known. These data indicate that a modest increase in acetaminophen sulfation, occurring alone following N-acetylcysteine treatment, is insufficient to explain the profound efficacy of the antidote in mice, and further suggest that this holds true for other species, such as humans, that are comparatively poor in the sulfoconjugation of acetaminophen.