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This study was undertaken to evaluate the early ultrastructural changes during the development of acetaminophen hepatotoxicity. Doses at or near the threshold for hepatotoxicity were selected to permit comparison of early reversible effects to those which ultimately progressed to necrosis in the absence of early agonal effects or drug-induced mortality. Both 300- and 600-mg/kg doses resulted in similar declines in hepatic glutathione levels to 14 and 22% of control values, respectively, by 2 hours, with more rapid recovery after the low dose. Plasma sorbitol dehydrogenase activity was elevated after 600 mg/kg but not after 300 mg/kg. During the first 2 hours after acetaminophen there was cytomegaly with rapid progression to necrosis after 600 mg/kg but minimal progression after 300 mg/kg. Ultrastructurally, vesiculation, vacuolation and mitochondrial and plasma membrane degeneration culminated in scattered single cell death by 4 hours and widespread centrilobular necrosis by 8 hours after 600 mg/kg. The time course of lesion development was slower after 300 mg/kg with damage restricted to the first two to three rows of centrilobular cells and limited numbers of isolated necrotic cells by 8 hours. By 18 to 24 hours livers of mice given 300 mg/kg appeared normal. Results are consistent with the endoplasmic reticulum being the site of acetaminophen activation and initial attack. However, early ultrastructural changes in mitochondria and plasma membrane observed after the high dose were not prominent after the low dose. This suggests that early acetaminophen damage to these organelles may play a critical role in acetaminophen hepatotoxicity.

Acetaminophen in acute overdose is primarily recognized as potentially hepatotoxic with few descriptions of extrahepatic lesions other than nephrotoxicity. Fasted adult, male mice, both standard and germ-free, were given acetaminophen orally and killed at selected times, from 30 minutes to 48 hours after treatment. In addition to the expected hepatic effects after 600 mg acetaminophen/kg, degenerative and necrotic changes were found in four non-hepatic tissues. Nephrosis developed 2 to 4 hours after treatment and paralleled the course of hepatic damage. Necrosis of bronchiolar epithelium in the absence of inflammation was evident 4 to 6 hours after acetaminophen administration as was onset of testicular changes. Spermatidic degeneration with early development of spermatidic multinucleated giant cells were characteristic features. Areas of lymphoid necrosis were also visible in splenic follicles and Peyer's patches 18 to 24 hours after treatment. These observations have demonstrated that other tissues in addition to liver and kidney are damaged by acetaminophen toxicity and should be considered in cases of acetaminophen overdosage.