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 -