TY - JOUR
T1 - Liver cytosol catalyzed conjugation of reduced glutathione with a reactive metabolite of acetaminophen
AU - Rollins, Douglas E.
AU - Buckpitt, Alan R
PY - 1979
Y1 - 1979
N2 - The effect of liver cytosol enzymes on the rate of formation of a glutathione (GSH) conjugate and on the rate of covalent binding of acetaminophen to microsomal proteins was studied in vitro. Mouse liver microsomes were incubated with [14C]acetaminophen, GSH, a NADPH-generating system, and Sephadex G-25-treated mouse liver supernatant. The addition of liver cytosol to the microsomal incubation increased the rate of conjugate production, as measured by high pressure liquid chromatography and decreased the rate of covalent binding of the reactive intermediate of acetaminophen to microsomal proteins at all concentrations of GSH and acetaminophen studied. The effect of the liver supernatant enzymes was most pronounced at low GSH concentrations. Although cysteine and N-acetyl-l-cysteine form conjugates with acetaminophen, the cytosol preparations did not facilitate conjugate formation with these nucleophiles. Cytosol enzymes may be important in the detoxification of acetaminophen particularly when the liver concentration of GSH is low and may contribute to the marked "threshold" effect seen with acetaminophen toxicity.
AB - The effect of liver cytosol enzymes on the rate of formation of a glutathione (GSH) conjugate and on the rate of covalent binding of acetaminophen to microsomal proteins was studied in vitro. Mouse liver microsomes were incubated with [14C]acetaminophen, GSH, a NADPH-generating system, and Sephadex G-25-treated mouse liver supernatant. The addition of liver cytosol to the microsomal incubation increased the rate of conjugate production, as measured by high pressure liquid chromatography and decreased the rate of covalent binding of the reactive intermediate of acetaminophen to microsomal proteins at all concentrations of GSH and acetaminophen studied. The effect of the liver supernatant enzymes was most pronounced at low GSH concentrations. Although cysteine and N-acetyl-l-cysteine form conjugates with acetaminophen, the cytosol preparations did not facilitate conjugate formation with these nucleophiles. Cytosol enzymes may be important in the detoxification of acetaminophen particularly when the liver concentration of GSH is low and may contribute to the marked "threshold" effect seen with acetaminophen toxicity.
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U2 - 10.1016/0041-008X(79)90328-4
DO - 10.1016/0041-008X(79)90328-4
M3 - Article
C2 - 452025
AN - SCOPUS:0018747255
VL - 47
SP - 331
EP - 339
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 2
ER -