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Toxic Doses of Acetaminophen Suppress Hepatic Glutathione Synthesis in Rats

✍ Scribed by Bernhard H. Lauterburg; Jerry R. Mitchell

Publisher: John Wiley and Sons
Year: 2007
Tongue: English
Weight: 563 KB
Volume: 2
Category: Article
ISSN: 0270-9139
DOI: 10.1002/hep.1840020103

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✦ Synopsis

The effect of a toxic dose of acetaminophen on hepatic glutathione turnover was studied in fed and fasted rats. Following the administration of 1 g m per kg of acetaminophen, the fractional rate of glutathione turnover increased from 0.19 to 0.28 hr-' in fed rats and from 0.43 to 0.50 hr-' in rats fasted for 48 hr. The increase in the fractional rate of turnover was proportionally much less than the decrease in hepatic glutathione concentration resulting from the toxic dose of acetaminophen. Thus, the estimated hepatic synthesis of glutathione decreased from 0.86 and 1.50 pmole per gm liver hr to 0.59 and 0.53 pmole per grll hr in fed and fasted rats, respectively. The excretion of acetaminophen-sulfate was significantly decreased in fasted rats. The fraction of administered acetaminophen metabolized to the mercapturic acid, however, was similar in both groups. Nevertheless, all fasted animals had massive centrilobular necrosis whereas virtually no necrosis was observed in fed animals. The administration of sulfate did not protect against liver injury in fasted rats. In view of the similar synthesis of glutathione in fed and fasted rats following a toxic dose of acetaminophen, an inability to synthesize adequate quantities of glutathione or a decreased availability of sulfate cannot account for the increased susceptibility to liver injury in the fasted state. However, a toxic dose of acetaminophen depletes the hepatic glutathione to a lower nadir before glutathione is repleted by synthesis, and a greater amount of tissue arylation occurs during this brief period of critically depleted glutathione. ''3"S-L-cysteine (27 mCi per mmoleT Corporation, Arlington Heights, 111. 1 and 20 mg Per kg of a&aminophen, bile was collected at intervals, and the spe-

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