TY - JOUR
T1 - Metabolites of acetaminophen trigger Ca2+ release from liver microsomes
AU - Stoyanovsky, Detcho A.
AU - Cederbaum, Arthur I.
N1 - Funding Information:
This work was supported by USPHS Grant AA-06610 from The National Institute on Alcohol Abuse and Alcoholism.
PY - 1999/5/20
Y1 - 1999/5/20
N2 - Release of mitochondrial calcium is believed to play a key role in the toxicity of acetaminophen in biological systems. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. The major metabolites of acetaminophen, benzoquinone imine and 1,4-benzoquinone, induced Ca2+ release in isolated rat liver microsomes. The 1,4-benzoquinone-induced release of calcium was suppressed by ryanodine and fully inhibited by reduced glutathione. Concentrations of 1,4-benzoquinone that induced Ca2+ release did not affect the activity of the microsomal Ca2+, Mg2+-APTase. The binding of [3H]ryanodine to liver microsomes, however, was significantly decreased by 1,4-benzoquinone, suggesting a direct interaction of this metabolite with the ryanodine-binding protein (ryanodine receptor). These results suggest that cellular Ca2+ levels may be elevated by acetaminophen by pathways involving, in part, activation of Ca2+ releasing channels such as the ryanodine receptor. Copyright (C) 1999 Elsevier Science Ireland Ltd.
AB - Release of mitochondrial calcium is believed to play a key role in the toxicity of acetaminophen in biological systems. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. The major metabolites of acetaminophen, benzoquinone imine and 1,4-benzoquinone, induced Ca2+ release in isolated rat liver microsomes. The 1,4-benzoquinone-induced release of calcium was suppressed by ryanodine and fully inhibited by reduced glutathione. Concentrations of 1,4-benzoquinone that induced Ca2+ release did not affect the activity of the microsomal Ca2+, Mg2+-APTase. The binding of [3H]ryanodine to liver microsomes, however, was significantly decreased by 1,4-benzoquinone, suggesting a direct interaction of this metabolite with the ryanodine-binding protein (ryanodine receptor). These results suggest that cellular Ca2+ levels may be elevated by acetaminophen by pathways involving, in part, activation of Ca2+ releasing channels such as the ryanodine receptor. Copyright (C) 1999 Elsevier Science Ireland Ltd.
KW - Acetaminophen
KW - Ca-release
KW - Liver microsomes
KW - Metabolites
UR - http://www.scopus.com/inward/record.url?scp=0032942437&partnerID=8YFLogxK
U2 - 10.1016/S0378-4274(99)00009-0
DO - 10.1016/S0378-4274(99)00009-0
M3 - Article
C2 - 10378447
AN - SCOPUS:0032942437
SN - 0378-4274
VL - 106
SP - 23
EP - 29
JO - Toxicology Letters
JF - Toxicology Letters
IS - 1
ER -