Posted on December 17, 2001 at 4:00 p.m.
BIRMINGHAM, AL — A drug currently used to treat gout might also relieve the intense pain of sickle cell disease, say researchers at UAB (University of Alabama at Birmingham). In a paper published in the December 18th issue of the Proceedings of the National Academy of Science, UAB researchers found that an enzyme called xanthine oxidase contributes to the circulatory disorders common to sickle cell patients. Allopurinol, a drug that inhibits xanthine oxidase, is already used for inhibiting the actions of xanthine oxidase in the treatment of gout.
“This discovery represents a quantum leap in our understanding of functional problems in the blood vessels of people with sickle cell disease” says Dr. Bruce Freeman, professor of anesthesiology at UAB and senior author of the paper. “By identifying the pathogenic roles played by xanthine oxidase, we have revealed a novel therapeutic “window” for understanding the pathogenesis and studying new approaches for the treatment of sickle cell disease.”
Blood cells in persons with sickle cell disease assume a rigid, sickle shape, instead of being round and flexible. The disease is marked by organ damage, strokes, acute respiratory disorders and intense episodes of joint pain and stiffness, all caused by sickled blood cells damaging the function of blood vessels. Once thought to be the result of red cell obstruction of blood flow in vessels, Freeman and colleagues are now appreciating that sickled red cells initiate a cascade of inflammatory responses that impair how vessels open and close upon demand.
Xanthine oxidase is principally present in the liver and intestines. The UAB researchers discovered that when the liver is damaged from sickle cell disease, xanthine oxidase is released from the liver into blood vessels. Once in the bloodstream, xanthine oxidase binds to the blood vessel walls and releases toxic oxygen by-products called free radicals. These reactive molecules then interfere with nitric oxide, a key mediator of blood vessel function.
“Nitric oxide is a necessary molecule for normal blood flow, by keeping vessels dilated and free of circulating white cells” says Dr. Mutay Aslan, a physician and doctoral student in biochemistry and molecular genetics at UAB who spearheaded the UAB research. “Xanthine oxidase present in the blood stream and on vessel walls will severely disrupt the normal operation of nitric oxide, leading to painful crises and other circulatory problems in sickle cell disease.”
Freeman says plans are under way to begin clinical trials of oxypurinol and allopurinol, which have long been used for the treatment of gout. Gout is caused by the presence of too much uric acid, another product of xanthine oxidase, in the blood stream and liver.
“Oxypurinol is an effective inhibitor of xanthine oxidase and the oxygen free radicals that it produces,” says Freeman. “If it works as we anticipate, it may even remove the xanthine oxidase from the blood stream by acting also at the level of the liver, and overall will hopefully lessen the painful episodes and other symptoms of sickle cell disease.”
Freeman and Aslan’s research was aided by collaborations with colleagues in the NIH-funded UAB Comprehensive Sickle Cell Disease Center, who provided a genetically-engineered strain of mice that have sickle cell disease, developed in 1997 by UAB researchers. Dr. Tim Townes, chairman of the department of biochemistry and molecular genetics, led a team that removed hemoglobin genes from mice and replaced them with human sickle cell hemoglobin genes, creating mice that had human sickle cell hemoglobin and all the traits of humans with sickle cell disease. That model, the first of its kind for sickle cell disease, has given researchers a way to understand problems associated with this disease and to test potential treatments.
Sickle cell disease is a hereditary disease most commonly found in people of African, Middle Eastern or Mediterranean descent. One in 500 African-Americans has sickle cell disease. The mutation that occurs in a the hemoglobin gene of sickle cell patients results in a minor modification of hemoglobin that causes red blood cells to sometimes take on a sickle shape, prohibiting them from moving easily through the body. The sickled red blood cells can cause anemia, organ damage and intense pain. Current life expectancy is around 40 years.
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