INHIBITION OF LDL OXIDATION AND MYELOPEROXIDASE DEPENDENT TYROSYL RADICAL FORMATION BY THE SELECTIVE ESTROGEN-RECEPTOR MODULATOR RALOXIFENE(LY139481 HCL)

Cellular oxidation of protein and lipoproteins is believed to contribu te to the pathology associated with both acute and chronic inflammator y processes. Enzymatic, myeloperoxidase and lipoxygenase, and non- enz ymatic oxidation of low density lipoprotein, LDL, has been implicated in foam cell formation and the progression of atherosclerotic changes within the arterial wall. In the present study, the in vitro protectiv e role of the selective estrogen receptor modulator, raloxifene, in th ese oxidant triggered processes has been investigated. Raloxifene, as with estrogen was observed to inhibit both copper mediated LDL oxidati on as well as the cellular modification of LDL by murine peritoneal ma crophages. Raloxifene was, however, a more potent inhibitor of LDL oxi dation than 17 beta-estradiol. The inhibition of macrophage LDL modifi cation by raloxifene was not due to a non- specific effect on all effe ctor functions as phagocytosis of opsonized yeast was comparable with control macrophage cultures. In addition to the protective effects on LDL oxidation, raloxifene also inhibited tyrosyl radical formation cat alyzed by myeloperoxidase. The inhibition of myeloperoxidase activity was observed for both the isolated enzyme and in phorbol ester stimula ted murine peritoneal neutrophils. In contrast, raloxifene was a weake r inhibitor of horseradish peroxidase. These results demonstrate a pot ential protective role for raloxifene as an anti-oxidant in in vitro a ssays designed to evaluate oxidant mediated radical formation and tiss ue damage.