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| |  New Mechanism To Explain Carbon Monoxide Poisoning Identified PHILADELPHIA, PA. – September 25, 1997 -- Researchers at the University of Pennsylvania Medical Center have discovered a novel biochemical mechanism for carbon monoxide (CO) poisoning that may someday lead to new clinical approaches for dealing with exposure to this deadly gas. The scientists report their findings, which challenge the textbook definition of CO toxicity, in this month’s issue of Chemical Research in Toxicology. Each year, carbon monoxide leads the list of causes of poison-related deaths in the United States. Thousands of people die annually from accidentally inhaling the tasteless and odorless gas. Major exposures to deadly levels of CO are associated with house fires, faulty furnaces and water heaters. However, CO is ubiquitous -- auto emissions and tobacco smoke account for much of the low-level exposures to which people are bombarded everyday. The physiological consequences of these sustained levels of CO exposure are virtually unknown. The classic explanation for CO's poisonous action is that it binds to hemoglobin molecules in the blood, impairing oxygen delivery to the body's cells. Eventually cells essentially suffocate and die. "This traditional view explains the mechanism of carbon-monoxide toxicity in only a small fraction of all people exposed to it," said senior author Stephen R. Thom, MD, PhD, associate professor of emergency medicine, and chief of hyperbaric medicine at Penn's Institute for Environmental Medicine. "The vast number of patients we see clearly don't fit this traditional explanation. Science falls down in terms of what we see in day-to-day practice." Now, Thom and Penn colleagues Harry Ischiropoulos, PhD, research assistant professor of biochemistry and biophysics, and Y. Anne Xu, research specialist in environmental medicine, have identified a mechanism that provides an alternate explanation for CO toxicity. "We found that carbon dioxide binds to the same sites on heme proteins as nitric oxide," Thom explained. Nitric oxide (NO) is a much-studied, naturally occurring vasodilator and gaseous signaling molecule. An excess of NO, however, is deleterious to brain cells and other tissues. "The amount of nitric oxide in the cell interior rises because carbon monoxide usurps the spot of nitric oxide on the heme proteins," Thom said. This imbalance makes NO available for biochemical reactions that would not normally occur within the cell, namely ones that produce tissue-damaging oxidants and free radicals. The team's experiments showed more NO being released by cells with exposure to greater and greater concentrations of CO. The cells eventually died. "This is the first time this mechanism of carbon- monoxide toxicity has been demonstrated," Thom added. In earlier studies, Thom found blood vessels are a major site of damage in the brain due to CO exposure, especially the cells that line the inner wall of the vessels, called the endothelium. This damage occurs relatively early during exposure to CO. Thom argued if damage occurs early on, it could also be happening with lower concentrations of CO over longer periods of time. "A lower dose of carbon monoxide showed a lower magnitude of cell death, but the important thing is that we still saw cell death," Thom said, adding he measured toxicity at levels lower than what typical smokers would have in their bodies and lower than in the air next to busy streets at rush hour. "The big picture is that we have identified a mechanism of how carbon monoxide can damage cells at levels that are relevant to real-world situations, and a mechanism that has nothing to do with classic hypoxia," Thom explained. On a more practical side, he hopes that the study's findings will convince the large number of physicians who tenaciously hold onto the classic explanation for carbon-monoxide toxicity that there is more than one way to explain this type of poisoning. “Hopefully this will improve our general understanding of what's going on in patients, and with that a greater sensitivity to the need to be more aggressive about prevention and treatment of carbon-monoxide exposure," he said.
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