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Tiny mutation might help indicate proper dosage for half of all drugs
Date:5/10/2010

COLUMBUS, Ohio A tiny gene mutation in human liver cells could one day influence how high or low a dose patients need of about half of the clinically used drugs on the market, new research suggests.

Scientists at Ohio State University and their colleagues have identified this mutation, and have shown that it alters the level of a protein in the liver responsible for processing between 45 percent and 60 percent of medications used to treat a wide range of conditions.

Each gene contains two alternative forms called alleles that are identical in most people. However, in this case, the researchers found that the activity level, or expression, of one allele differs from its partner allele in a single gene. That small difference is called a single nucleotide polymorphism, or SNP (pronounced snip).

This SNP affects the gene's protein-producing process, in turn lowering the level of an enzyme known as CYP3A4.

The faster a drug is processed, or metabolized, by this enzyme in the liver, the more quickly it is eliminated from that tissue and the body as a whole. When this enzyme level is lowered by the presence of this SNP, people are likely to require smaller doses of medicines that the enzyme metabolizes. But this also means that higher doses of these same drugs can be dangerous to people with the mutation if those levels become toxic.

The study further showed that people with the mutation who take a certain class of cholesterol-lowering drugs do indeed require lower doses of these medications to achieve the same effect that higher doses produce in people without the SNP.

The researchers suggest that this mutation could serve as a molecular biomarker to aid doctors in clinical practice, affecting dosing requirements, patients' response to medications and toxicity levels of numerous drugs, especially anti-cancer medications.

"With some cancer drugs, there is a very narrow therapeutic index, meaning tha
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Contact: Danxin Wang
wang.808@osu.edu
614-292-7336
Ohio State University
Source:Eurekalert

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