Metabolites of acetaminophen trigger Ca2+ release from liver microsomes.
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.
Stoyanovsky
D A
DA
Department of Biochemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cederbaum
A I
AI
D000082:Acetaminophen / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism*; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D007097:Imines / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D012433:Ryanodine; D000082:Acetaminophen; C004532:quinone; D017301:Ca(2+) Mg(2+)-ATPase; C028473:N-acetyl-4-benzoquinoneimine; D002118:Calcium