Acetaminophen-Induced Hepatic Necrosis: A Reminiscence

In the early 1970s, Dr. B. B. Brodie, head of the Laboratory of Chemical Pharmacology, National Heart Institute, National Institutes of Health, initiated a program to elucidate the mechanism of hepatic necrosis induced in rats by bromobenzene. These studies showed a crucial role for its 3,4-epoxide intermediate, known in part, to collapse to 4-bromophenol. To examine a possible contribution of this phenol to tissue toxicity, some rats were coadministered a high dose of acetaminophen to suppress phenolic clearance by glucuronidation and sulfation. Subsequent examination of liver slices showed that the acetaminophen-only control rats had extensive centrilobular liver necrosis. This article is a personal reminiscence of the events that led up to this accidental observation, how it happened, and the subsequent resolution of the underlying mechanism, including the covalent binding of NAPQI to liver protein as the initial "hit," the glutathione protective threshold, the antidotal activity of cysteine, and the existence of the "therapeutic window" for antidotal therapy. Collectively, these studies formed the basis for antidotal therapy of acetaminophen overdose patients. SIGNIFICANCE STATEMENT: Studies in the early 1970s extended Dr. B. Brodie's "Reactive Metabolites as a Cause of Tissue Injury" concept to explain the initial events leading to fulminant hepatic necrosis seen after overdoses of acetaminophen. This article, written by one of the key contributors, is a reminiscence of how the studies originated, how they were developed, and their significance for therapy.