Finding sheds light on drug toxicity

Related tags Acute lymphoblastic leukemia

Researchers in the US have uncovered the mechanism underlying a
genetic tendency for some patients to be more susceptible to side
effects of drugs than others.

The scientists, from the Mayo Clinic, said the mechanism decreases a protein and in turn causes certain individuals to metabolise thiopurine drugs differently.

Thiopurine therapies are used to treat patients with childhood leukaemia, 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.

For example, 85 per cent of children who are diagnosed with acute lymphoblastic leukaemia, the most common childhood cancer, are cured of the disease. Unfortunately, the drugs which have made this possible - including the thiopurine 6-mercaptopurine - can also have severe side effects, occasionally resulting in death.

In the current issue of the Proceedings of the National Academy of Sciences, the researchers report that under certain genetic conditions, key proteins are not formed properly and 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 trashcan known as an aggresome. 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 metabolises 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,"​ said Liewei Wang, the 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."

The findings related to the aggresome are just the latest in a series of discoveries at the Mayo that have brought it to the forefront of pharmacogenomics research. 20 years ago, Mayo researchers developed a genetic test, measuring an individual's ability to produce an enzyme involved in the metabolism of thiopurine drugs. This test allowed treatment with the drugs to be tailored to a level that avoided side effects, in what is considered the first application of pharmacogenomics in a clinical setting.

"Nobody has shown before that the aggresome plays a role in thiopurine metabolism, and it's a significant contribution,"​ said Richard Weinshilboum, the Mayo Clinic researcher who first described the genetically variable response to thiopurine drugs over 20 years ago.

"From a clinical point of view, the genetic test we developed at Mayo to predict response to thiopurine drugs has been invaluable to pharmacogenomic medicine -- and now this finding is taking us in promising new directions because we believe our findings can be generalised to apply to many instances in the field."

The finding helps explain what goes wrong under certain genetic conditions - and suggests mechanisms which might help predict which genetic changes could alter the effect of drugs. Prior efforts to explain the mystery of thiopurine metabolism had focused on biochemical mechanisms - not changes in protein levels.

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