CLINICAL PHARMACOLOGY OF LIPID PEROXIDATION AND ANTIOXIDANT AGENTS

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Free radicals have been implicated in an increasing large number of human diseases. Recently we discovered a series of prostaglandin F2-like compounds, termed F2-Isoprostanes (F2-Isop) that are produced independently of the cyclooxygenase enzyme by free radical catalyzed peroxidation of arachidonic acid. F2-Isop['s are formed in situ esterified to phospholipids and released preformed. We have accumulated considerable evidence indicating that measurement of F2-Isop represents an important advance in our ability to assess oxidative stress status in humans. One study is proposed to enhance our ability to assess endogenous production of F2Isop's by measuring a urinary metabolite of the F2-Isop, 8- iso-PGF2alpha. Toward this goal, we plan to determine the metabolic fate of 8-iso-PGF2alpha in the monkey as a basis for the future development of a mass spectrometric assay for a urinary metabolite of 8-iso-PGF2alpha. One of major areas under consideration for human trials of antioxidant therapy with vitamin C, vitamin E, and beta-carotene is in the prevention of atherosclerosis. However, the clinical pharmacology of these agents has not been defined. We have found that patients with hyperlipidemia, have elevated levels of P2-Isop's esterified to plasma lipids. Thus, a study is proposed to establish the dose-dependent effects of these agents given singly and in combination in patients with hyperlipidemia. An impressive amount of evidence has suggested that oxidation of LDL is a key event in atherogenesis that converts LDL to a form that is taken up by macrophages, leading to foam cell formation. In cholesterol fed rabbits, an animal model of atherosclerosis, levels of F2-Isop's esterified to plasma lipids are markedly increased and are suppressed by the antioxidant, BHT. Studies are thus proposed to determine, using varying doses of vitamins C and E and beta-carotene, if levels of F2-Isop's esterified to plasma lipids in these animals predict and correlate with what occurs in the vascular wall, i.e. oxidation of lipids and extent of atherosclerosis. A role for the 12/15-lipoxygenase in the cellular oxidation of LDL has been suggested, although not proven. Another study is proposed to determine whether the oxidation of lipoproteins and the extent of atherosclerosis is reduced in Apo-E deficient mice, a mouse model of atherosclerosis, that have been mated with 12/15-lipoxygenase deficient mice and also in single 12/15 lipoxygenase deficient mice fed an atherogenic diet.