In Vitro Reactivity of Carboxylic Acid-CoA Thioesters with Glutathione
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In Vitro Reactivity of Carboxylic Acid-CoA Thioesters with Glutathione. / Sidenius, Ulrik; Skonberg, Christian; Olsen, Jørgen; Hansen, Steen Honore'.
In: Chemical Research in Toxicology, Vol. 17, No. 1, 2004, p. 75-81.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - In Vitro Reactivity of Carboxylic Acid-CoA Thioesters with Glutathione
AU - Sidenius, Ulrik
AU - Skonberg, Christian
AU - Olsen, Jørgen
AU - Hansen, Steen Honore'
PY - 2004
Y1 - 2004
N2 - The chemical reactivity of acyl-CoA thioesters toward nucleophiles has been demonstrated in several recent studies. Thus, intracellularly formed acyl-CoAs of xenobiotic carboxylic acids may react covalently with endogenous proteins and potentially lead to adverse effects. The purpose of this study was to investigate whether a correlation could be found between the structure of acyl-CoA thioesters and their reactivities toward the tripeptide, glutathione (ç-Glu-Cys-Gly). The acyl-CoA thioesters of eight carboxylic acids (ibuprofen, clofibric acid, indomethacin, fenbufen, tolmetin, salicylic acid, 2-phenoxypropionic acid, and (4-chloro-2-methyl-phenoxy)acetic acid (MCPA)) were synthesized, and each acyl-CoA (0.5 mM) was incubated with glutathione (5.0 mM) in 0.1 M potassium phosphate (pH 7.4, 37 °C). All of the acyl-CoAs reacted with glutathione to form the respective acyl-S-glutathione products, with MCPA-CoA having the highest rate of conjugate formation (120 ( 10 íM/min) and ibuprofen-CoA having the lowest (1.0 ( 0.1 íM/min). The relative reactivities of the acyl-CoAs were dependent on the substitution at the carbon atom R to the acyl carbon and on the presence of an oxygen atom in a position â to the acyl carbon and were as follows: phenoxyacetic acid > o-hydroxybenzoic acid phenoxypropionic acid > arylacetic acid derivatives > 2-methyl-2-phenoxypropionic acid 2-phenylpropionic acid. For each acyl-CoA thioester, the overallhydrolysis rate was determined as the time-dependent formation of parent compound. A linear trend was observed when comparing the reactivities of the acyl-CoAs with glutathione with the corresponding overall hydrolysis rates. Thus, the most reactive compound (MCPA-CoA) was also the compound with the highest rate of hydrolysis and the least reactive compounds (ibuprofen-CoA, clofibryl-CoA) were also the compounds least susceptible to hydrolysis.
AB - The chemical reactivity of acyl-CoA thioesters toward nucleophiles has been demonstrated in several recent studies. Thus, intracellularly formed acyl-CoAs of xenobiotic carboxylic acids may react covalently with endogenous proteins and potentially lead to adverse effects. The purpose of this study was to investigate whether a correlation could be found between the structure of acyl-CoA thioesters and their reactivities toward the tripeptide, glutathione (ç-Glu-Cys-Gly). The acyl-CoA thioesters of eight carboxylic acids (ibuprofen, clofibric acid, indomethacin, fenbufen, tolmetin, salicylic acid, 2-phenoxypropionic acid, and (4-chloro-2-methyl-phenoxy)acetic acid (MCPA)) were synthesized, and each acyl-CoA (0.5 mM) was incubated with glutathione (5.0 mM) in 0.1 M potassium phosphate (pH 7.4, 37 °C). All of the acyl-CoAs reacted with glutathione to form the respective acyl-S-glutathione products, with MCPA-CoA having the highest rate of conjugate formation (120 ( 10 íM/min) and ibuprofen-CoA having the lowest (1.0 ( 0.1 íM/min). The relative reactivities of the acyl-CoAs were dependent on the substitution at the carbon atom R to the acyl carbon and on the presence of an oxygen atom in a position â to the acyl carbon and were as follows: phenoxyacetic acid > o-hydroxybenzoic acid phenoxypropionic acid > arylacetic acid derivatives > 2-methyl-2-phenoxypropionic acid 2-phenylpropionic acid. For each acyl-CoA thioester, the overallhydrolysis rate was determined as the time-dependent formation of parent compound. A linear trend was observed when comparing the reactivities of the acyl-CoAs with glutathione with the corresponding overall hydrolysis rates. Thus, the most reactive compound (MCPA-CoA) was also the compound with the highest rate of hydrolysis and the least reactive compounds (ibuprofen-CoA, clofibryl-CoA) were also the compounds least susceptible to hydrolysis.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/tx034127o
DO - 10.1021/tx034127o
M3 - Journal article
C2 - 14727921
VL - 17
SP - 75
EP - 81
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 1
ER -
ID: 20197096