ACETAMINOPHEN-INDUCED HEPATIC NECROSIS. I. ROLE OF DRUG METABOLISM

TLDR

Massive acetaminophen overdoses cause fulminant hepatic necrosis in humans, a phenomenon also observed in experimental animals. The study seeks to determine whether acetaminophen-induced hepatotoxicity is mediated by a toxic metabolite and proposes that such a metabolite underlies the necrosis. Researchers compared tissue acetaminophen concentrations with liver damage severity after manipulating metabolic rates using phenobarbital, piperonyl butoxide, 3‑methylcholanthrene, and cobaltous chloride. Dose‑dependent centrilobular necrosis was observed in mice and rats; phenobarbital accelerated metabolism yet worsened necrosis, whereas piperonyl butoxide and cobaltous chloride inhibited metabolism and protected against damage, while 3‑methylcholanthrene potentiated necrosis.

Abstract

A number of recent reports indicate that massive overdoses of acetaminophen can produce a fulminant hepatic necrosis in man. Acetaminophen-induced hepatic necrosis thereforne was examised in experimental animals. Centrilobular hepatic necrosis similar to that seen in man was shown to be dose dependent in mice and rats. To determine whether acetaminophen-induced hepatotoxicity was mediated throug an active metabolite, acetaminophen concentrations in rat and mouse tissues were compared with the severity of liver damage after alteration of the rate of metabolism of acetaminophen. Phenobarbital pretreatment stimulated the disappearance of acetaminophen from tissues but markedly potentiated the hepatic necrosis. In contrast, piperonyl butoxide pretreatment inhibited the metabolism and disappearance of acetaminophen from tissues yet dramatically protected against hepatic necrosis. Additional studies demonstrated that pretreatment with 3-methylcholanthrene also potentiated acetaminophen-induced hepatic necrosis whereas cobaltous chloride, which inhibits synthesis of cytochrome P-450, prevented the hepatic damage. We propose that acetaminophen-induced hepatic necrosis is mediated by a toxic metabolite of acetaminophen.