Little yellow molecule comes up big

November 25, 2002

Bilirubin has been a mystery of a molecule, associated with better health if there's just a little more than normal, but best known for being at the root of the yellow color in jaundice and, at high levels, for causing brain damage in newborns. Johns Hopkins scientists have now solved the enigma of how this toxic molecule can also be beneficial.

In the current online edition of the Proceedings of the National Academy of Sciences, the research team reports that bilirubin and the enzyme that makes it appear to be the body's most potent protection against oxidative damage. The finding may one day help improve treatment of stroke, heart attack and even cognitive decline following heart bypass surgery.

"So potent an anti-oxidant is bilirubin that it displaces glutathione, the molecule believed for 80 years to be the most important cellular anti-oxidant," says Solomon Snyder, M.D., director of neuroscience at the Johns Hopkins School of Medicine.

"There are some very elegant studies in the literature that tie slightly elevated bilirubin levels to better alertness in newborns, a lower risk of coronary artery disease and cancer in adults, and less damage from stroke in animal models. But these findings went against what people thought they knew about bilirubin, and the results were largely shrugged off," adds Snyder. "Now they make sense."

Known as the toxic yellow molecule at the end of the biologic degradation of hemoglobin, the "red" in red blood cells, bilirubin also has long been known to react with the highly reactive forms of oxygen responsible for practically all cellular damage. However, there's so little bilirubin in cells -- roughly a thousand times less than the amount of oxidants -- that it wasn't thought to actually contribute to cells' protection.

To test their idea that these tiny amounts of bilirubin had a big job, the scientists used a research tool called RNA interference to "zip up" the RNA for biliverdin reductase, the enzyme that makes bilirubin. Because the cell then can't use the RNA's instructions to make a protein, the result is the laboratory-dish equivalent of "knocking out" a gene.

Led by M.D./Ph.D. candidate David Baraño, the research team demonstrated that, without biliverdin reductase, human cancer cells and brain cells from rats experienced much more damage and cell death in response to small amounts of hydrogen peroxide, an oxidant, than cells with the enzyme intact.

Amazingly, the damage from knocking out the enzyme, and hence bilirubin, was even greater than knocking out the previously known cellular anti-oxidant, glutathione. While it takes one glutathione molecule to consume an oxidant, a single bilirubin molecule can take care of 10,000 oxidant molecules, the scientists found.

The key is that bilirubin is part of a cycle, so a single molecule can be used over and over again to scavenge highly reactive oxygen (free radicals) that otherwise would damage cells' membranes and their DNA beyond repair, the researchers say.

"An oxidant reacts with bilirubin to make biliverdin, which is then converted back into bilirubin by biliverdin reductase," says Snyder, who suggests bilirubin may protect cell membranes while glutathione may protect items inside cells. "One oxidant down, ten thousand to go."

The findings also settle a long-standing paradox -- why bilirubin is made at all. If the degradation of hemoglobin stopped one step earlier, with a greenish, soluble molecule called biliverdin, the waste could be easily excreted without the threat of damaging build-up, notes Snyder. But instead of stopping at biliverdin, most animal cells (except birds) continue on to make bilirubin using biliverdin reductase.

"If all bilirubin does is become toxic in high amounts, it doesn't make sense that animals would have developed its production at all, especially for a process as routine as degrading hemoglobin," says Snyder. "But oxidative stress is behind almost all cellular damage and death, from inflammation to heart attack and stroke. As a very elegant and potent way to protect cells from this stress, bilirubin is likely an important evolutionary development."

To reap the benefits of bilirubin's power to protect cells, researchers could develop agents that stimulate its release from blood cells, that temporarily prevent its clearance from the body, or that otherwise elevate the amount of bilirubin in the body. However, whether the approach would reduce cellular damage from heart attack or stroke, for example, remains to be seen.
Authors on the study are Baraño, Snyder and Mahil Rao of the Johns Hopkins School of Medicine; and Christopher Ferris, formerly of Hopkins and now at Vanderbilt University School of Medicine. The studies were funded by the U.S. Public Health Service.

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