THE PHARMACOLOGY OF INHIBITORS OF HEME PROTEIN-CATALYZED LIPID PEROXIDATION

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