REGULATORY EFFECTS OF HEME TRANSPORT INTO LIVER CELLS

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DESCRIPTION: Hemopexin, a plasma glycoprotein, transports heme into liver cells by a specific, receptor-mediated process. Heme oxygenase, a microsomal membrane enzyme, catalyzes the initial and rate-limiting step in heme degradation. The iron molecule released from heme is deposited on ferritin clusters. The concerted action of these proteins permits conservation of biologically useful iron, prevents accumulation of toxic heme molecules and inhibits the growth of invading microorganisms. The long-term objective of our research is to better understand the processes of heme and iron metabolism, with particular emphasis on the role of hemopexin and heme oxygenase in maintaining heme and iron homeostasis under adverse conditions (e.g., during intravascular hemolysis due to hereditary disorders and/or bacterial or viral infections or cellular stress caused by environmental toxins). One aspect of this research program is the biochemical characterization of the mechanism of heme oxygenase gene activation in response to the substrate heme and stress-associated agents. Regulation of heme oxygenase by heme is the focus of the current proposal. The specific aims of this proposal, which represents a logical extension of the studies carried out in the past three years since the last competitive review, are 1) to define the minimal heme-responsive element (HRE) by mutational analysis: functional and protein binding studies. 2) to isolate and characterize the HRE binding proteins (HRE-BPs) and their corresponding cDNA clones. 3) to determine which HRE-BPs mediate heme responsiveness by inhibition of specific HRE-BP expression (i.e., identification of the heme-response factor). A common feature among heme and other inducers of heme oxygenase is that they generate intracellular oxidative stress. Since pro-oxidants (or oxidative states) have been implicated in a plethora of human pathologies including atherosclerosis, ischemia/reoxy-genation, injury, and cancer, the results from the present studies should further our knowledge of the basic biology of these diseases.