THE PHARMACOLOGY OF INHIBITORS OF HEME PROTEIN-CATALYZED LIPID PEROXIDATION

Vanderbilt University, Nashville TN

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Abstract

Hemoprotein- catalyzed lipid peroxidation contributes to the pathophysiology of diseases in which myoglobin[unreadable] and hemoglobin are released from the antioxidant environment of cells. These include a major contribution[unreadable] of myoglobin-catalyzed lipid peroxidation to the renal failure produced by rhabdomyolysis and to[unreadable] microvascular constriction in myocardial ischemia. Lipid peroxidation induced by hemoglobin is correlated[unreadable] with the pathophysiology of subarachnoid hemorrhage, Falciparum malaria and sickle cell disease. Among[unreadable] the products of lipid peroxidation are the F2 -isoprostanes, which are highly potent vasoconstrictors. We[unreadable] have demonstrated that lipid peroxidation catalyzed by the peroxidase-like function of oxidized hemoproteins[unreadable] is inhibited by acetaminophen. In a rat model of rhabdomyolysis in which F2-isoprostanes generated[unreadable] intrarenally contribute to the renal failure, acetaminophen significantly reduced lipid peroxidation and[unreadable] markedly decreased the extent of renal failure. These findings provide a rationale for development of even[unreadable] more potent inhibitors. Compounds with lower ionization potential and bond dissociation enthalpy have been[unreadable] synthesized and found to have markedly increased potency as reductants of the ferryloxo radical of[unreadable] myoglobin and hemoglobin. Further testing of these compounds and synthesis of newer compounds in the[unreadable] series is proposed. The hypothesis that optimal inhibition of lipid peroxidation can be achieved by a[unreadable] combination of water soluble antioxidants that inhibit the radical initiator together with lipid soluble[unreadable] antioxidants that are chain breaking will be examined. The effect of acetaminophen will be evaluated in[unreadable] subarachnoid hemorrhage, in which evidence of lipid peroxidation correlates with time of delayed vasospasm[unreadable] and with severity of neurological deficits. This will be a pilot study in which acetaminophen based regimens[unreadable] will be tested for their ability to reduce lipid peroxidation assessed by measurement of F2 isoprostane levels[unreadable] in cerebrospinal fluid. Secondary endpoints will include vasospasm and brain ischemia as determined by[unreadable] magnetic resonance arteriography and imaging, as well as assessment of neurological outcome. The results[unreadable] could provide a basis for a larger outcome study, and a rationale for development of even more potent[unreadable] regimens for inhibiting hemoprotein-catalyzed lipid peroxidation in subarachnoid hemorrhage as well as in[unreadable] other diseases.