Clotrimazole enhances lysis of human erythrocytes induced by t-BHP.
Clotrimazole (CLT) is an antifungal and antimalarial agent also effective as a Gardos channel inhibitor. In addition, CLT possesses antitumor properties. Recent data provide evidence that CLT forms a complex with heme (hemin), which produces a more potent lytic effect than heme alone. This study addressed the effect of CLT on the lysis of normal human erythrocytes induced by tert-butyl hydroperoxide (t-BHP). For the first time, it was shown that 10 microM CLT significantly enhanced the lytic effect of t-BHP on erythrocytes in both Ca(2+)-containing and Ca(2+)-free media, suggesting that the effect is not related to Gardos channels. CLT did not affect the rate of free radical generation, the kinetics of GSH degradation, methemoglobin formation and TBARS generation; therefore, we concluded that CLT does not cause additional oxidative damage to erythrocytes treated with t-BHP. It is tempted to speculate that CLT enhances t-BHP-induced changes in erythrocyte volume and lysis largely by forming a complex with hemin released during hemoglobin oxidation in erythrocytes: the CLT-hemin complex destabilizes the cell membrane more potently than hemin alone. If so, the effect of CLT on cell membrane damage during free-radical oxidation may be used to increase the efficacy of antitumor therapy.
Lisovskaya
Irene L
IL
National Scientific Centre for Hematology of Russian Academy of Medical Sciences, Russia. irene l@mail.ru
Shcherbachenko
Irina M
IM
Volkova
Rimma I
RI
Ataullakhanov
Fazoil I
FI
D002118:Calcium / Q000378:metabolism; D003022:Clotrimazole / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006427:Hemin / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D018384:Oxidative Stress; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000737:chemistry / Q000494:pharmacology*
D006454:Hemoglobins; D017392:Thiobarbituric Acid Reactive Substances; D006427:Hemin; D020122:tert-Butylhydroperoxide; D003022:Clotrimazole; D005978:Glutathione; D002118:Calcium