TY - JOUR
T1 - Renal necrosis, glutathione depletion, and covalent binding after acetaminophen
AU - McMurtry, Randolph J.
AU - Snodgrass, Wayne R.
AU - Mitchell, Jerry R.
N1 - Funding Information:
This hypothesis is supported by evidence that a metabolite of acetaminophen becomes covalently bound to renal and hepatic macromolecules in uivo. The importance of metabolite covalent binding in the pathogenesis of hepatic and renal damage is supported by the relatively large amount of binding and the dose dependence of both binding of radiolabeled material and of necrosis (with binding preceding detectable necrosis by several hours). Further support is provided by the parallel alterations in the severity of necrosis and the extent of covalent binding following pretreatments that change drug metabolism, and the correlation between the severity of hepatic necrosis in individual animals and the extent of covalent binding of radiolabeled material in those animals.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1978/10
Y1 - 1978/10
N2 - A dose-dependent, acute renal necrosis occurred in male Fischer rats following a single subcutaneous injection of acetaminophen. Doses of [3H]acetaminophen (750-900 mg/kg) causing renal and hepatic necrosis in rats markedly depleted target organ glutathione and resulted in large amounts of radiolabeled metabolite being bound to renal and hepatic protein. Pretreatment with cobalt chloride, an inhibitor of hepatic and renal drug metabolism, decreased both the irreversible binding of metabolite and the glutathione depletion in target organ tissues while concomitantly protecting against tissue damage. Pretreatment with 3-methylcholanthrene enhanced hepatic necrosis and covalent binding of metabolite to hepatic protein in vivo and to microsomal protein in vitro but had little effect on the corresponding renal parameters. Covalent binding of radiolabeled acetaminophen to rat renal or hepatic microsomes was enzyme dependent and required NADPH and oxygen. Thus, acetaminophen-induced renal and hepatic necrosis apparently result from in situ activation of acetaminophen to a chemically reactive species capable of covalently binding to target organ macromolecules.
AB - A dose-dependent, acute renal necrosis occurred in male Fischer rats following a single subcutaneous injection of acetaminophen. Doses of [3H]acetaminophen (750-900 mg/kg) causing renal and hepatic necrosis in rats markedly depleted target organ glutathione and resulted in large amounts of radiolabeled metabolite being bound to renal and hepatic protein. Pretreatment with cobalt chloride, an inhibitor of hepatic and renal drug metabolism, decreased both the irreversible binding of metabolite and the glutathione depletion in target organ tissues while concomitantly protecting against tissue damage. Pretreatment with 3-methylcholanthrene enhanced hepatic necrosis and covalent binding of metabolite to hepatic protein in vivo and to microsomal protein in vitro but had little effect on the corresponding renal parameters. Covalent binding of radiolabeled acetaminophen to rat renal or hepatic microsomes was enzyme dependent and required NADPH and oxygen. Thus, acetaminophen-induced renal and hepatic necrosis apparently result from in situ activation of acetaminophen to a chemically reactive species capable of covalently binding to target organ macromolecules.
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U2 - 10.1016/0041-008X(78)90139-4
DO - 10.1016/0041-008X(78)90139-4
M3 - Article
C2 - 725953
AN - SCOPUS:0018081508
SN - 0041-008X
VL - 46
SP - 87
EP - 100
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 1
ER -