Cytotoxicity of myeloperoxidase-activated catechols: oxidative injury to the red blood cell.
The effects of two catechols (1,2-benzenediol and nordihydroguaiaretic acid) on the myeloperoxidase-Cl(-)-H2O2 antimicrobial/cytotoxic system of the human neutrophil were investigated. To determine the cytotoxicity of myeloperoxidase-generated oxygen metabolites (mainly chlorinated oxidants such as hypochlorite) and catechol oxidation products, the well characterized erythrocyte was used as a target. At relatively low concentrations (less than 10 microM), the catechols acted as redox catalysts by stimulating the generation of chlorinated oxidants. This is visualized as a promotion of haemolysis which reached a maximum and then decreased again with increasing concentrations of the catechol. In this respect, the dicatechol, nordihydroguaiaretic acid, was more potent. At higher concentrations, the catechols competed more effectively with Cl- as electron donors and the generation of chlorinated oxidants decreased with a consequent decrease in haemolysis. Above 200 microM nordihydroguaiaretic acid, complete haemolysis occurred which might be due to high membrane concentrations of the catechol due to its high lipid solubility. In contrast, high 1,2-benzenediol concentrations did not induce haemolysis. The catechols stimulated methaemoglobin formation in a concentration-dependent fashion with 1,2-benzenediol more potent than nordihydroguaiaretic acid. There was some correlation between membrane microviscosity and haemolysis which in turn did not correlate with haemoglobin oxidation. No direct correlation existed between intracellular methaemoglobin formation and the precipitation of haemoglobin oxidation products on the membrane. Disulphide crosslinks were not involved in the covalent polymerization of haemoglobin subunits.
van Zyl
J M
JM
Department of Pharmacology, Medical School, University of Stellenbosch, Tygerberg, South Africa.
Basson
K
K
Kriegler
A
A
van der Walt
B J
BJ
D002396:Catechols / Q000633:toxicity*; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects* / Q000648:ultrastructure; D006418:Heme / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D009637:Masoprocol / Q000633:toxicity; D008565:Membrane Proteins / Q000032:analysis; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
D002396:Catechols; D006454:Hemoglobins; D008565:Membrane Proteins; D006418:Heme; D012965:Sodium Chloride; D009637:Masoprocol; D009195:Peroxidase; C034221:catechol