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In vitro evidence of the inhibitory capacity of chloroquine on arginase activity in sickle erythrocytes
Author(s) -
Iyamu Efemwonkiekie W.,
Ekekezie Chiazotam,
Woods Gerald M.
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06798.x
Subject(s) - arginase , chloroquine , pharmacology , inhibitory postsynaptic potential , non competitive inhibition , in vitro , ic50 , chemistry , medicine , immunology , enzyme , biochemistry , malaria , arginine , amino acid
Summary Increased levels of erythrocyte arginase activity are believed to play a key role in the pathogenesis of sickle cell disease (SCD). Because increased arginase activity has been implicated in the exacerbation of pulmonary hypertension in SCD, this enzyme is considered an important therapeutic target for identifying new drugs to treat and manage SCD and other inflammatory disorders. Although chloroquine (CQ) is prescribed as an anti‐malarial and anti‐rheumatoid drug, the mechanism of its anti‐inflammatory activity is largely unknown. The present study found that CQ inhibited arginase in a dose‐dependent manner, and also displayed a linear competitive inhibition on sickle erythrocyte arginase. The apparent K M values in the presence of inhibitor were considerably reduced at both physiological and slightly acidic pHs. Slope replots of the double reciprocal plots at pH 6·8 and 7·4 also indicated simple competitive inhibitory mechanism of CQ, and K i values for CQ were within micromolar levels. To our knowledge, this is the first example of an anti‐malarial and anti‐inflammatory agent displaying competitive inhibition kinetics on arginase. The outcome of this study may provide a template for the rational design of specific agents either alone or in combination with CQ for the inhibition of arginase activity.