Relationship between sulfotransferase activity and susceptibility to acetaminophen-induced liver necrosis in the hamster
Miller, M.G.; Jollow, D.J.
Drug Metabolism and Disposition the Biological Fate of Chemicals 15(2): 143-150
1987
ISSN/ISBN: 0090-9556 PMID: 2882969 Document Number: 301956
The effect of pretreatments which modulate acetaminophen sulfotransferase activity on the hepatotoxicity of acetaminophen have been examined in the hamster. Co-administration of sodium sulfate modestly enhanced the formation of acetaminophen sulfate, but provided little protection against liver injury. In isolated hepatocyte studies, sodium sulfate enhanced the Vmax of acetaminophen sulfotransferase activity, but did not alter the apparent Km toward acetaminophen. Administration of 2,6-dichloro-4-nitrophenol with acetaminophen selectively depressed acetaminophen sulfate formation in vivo and significantly exacerbated acetaminophen hepatotoxicity. In kinetic studies using isolated hamster hepatocytes, 2,6-dichloro-4-nitrophenol competitively inhibited acetaminophen sulfotransferase with a Ki of 2.5 X 10(-6) M. The data indicate that in the hamster, acetaminophen sulfotransferase activity plays a relatively minor role in the modulation of acetaminophen hepatotoxicity, and that, at hepatotoxic doses, the capacity limitation on this enzyme system is determined to a greater extent by its Km (app) value than by limitation in cofactor (3'-phosphoadenosine 5'-phosphosulfate) availability.