Genomics Researchers Discover Protein Deficit That Causes Drug Toxicity

Mayo Clinic researchers have discovered an inherited structural mechanism that can make drugs for some diseases toxic for some patients. The mechanism decreases a protein and in turn causes certain individuals to metabolize thiopurine drugs differently. Thiopurine therapies are used to treat patients with childhood leukemia, autoimmune diseases and organ transplants. The Mayo researchers say their finding advances the field of pharmacogenomics, which tailors medicine to a patient's personal genetic makeup. In the current issue of the Proceedings of the National Academy of Sciences, (http://www.pnas.org/cgi/content/abstract/102/26/9394) Mayo researchers report that under certain genetic conditions, key proteins are not formed properly -- they are "misfolded." When misfolding happens, the quality-control process in the cell detects the misfolded proteins and tags them for immediate destruction or quarantines them in a "cellular trash can" known as an aggresome (last syllable rhymes with "foam"). Whether destroyed or aggregated into the aggresome, the effect is the same: the patient's body suffers a protein deficit that disrupts the enzyme that metabolizes thiopurine. "Our finding is surprising because the aggresome is a new kind of mechanism to study to explain this. It's quite different from what we were thinking even a few years ago," says Liewei Wang, M.D., Ph.D., lead Mayo researcher in the study. "People are still debating what its function really is, but it appears to play a role here by receiving misfolded proteins."

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