An April 18 Health article incorrectly stated that the cytochrome P450 (CYP) family of enzymes processes 25 percent of all drugs. CYP enzymes process most drugs. The same story mistakenly described Laboratory Corporation of America Holdings, or LabCorp, as a subsidiary of Roche Diagnostics.
Liver Success
Emerging Enzyme Test Can Predict Drug Side Effects
Tuesday, April 18, 2006; Page HE01
Adverse drug reactions -- what most of us call side effects -- can range from annoying (headaches) to debilitating (diarrhea, vomiting) to deadly. And certain drugs -- especially psychiatric and cardiac ones -- are more apt to cause severe reactions. If only doctors had a way to predict who's most susceptible.
In many cases, they do, just by conducting a blood test or cheek swab before writing a prescription.
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Researchers in the growing field of pharmacogenetics -- the study of how people's genetic make-up affects their response to medicines -- say doctors can screen for genetic variations that often prevent liver enzymes from processing certain drugs properly. When that occurs, a dose may not register at all -- or it may produce a toxic reaction. Cost for the one-time screening? Between $200 and $1,400.
David Mrazek, chairman of psychiatry and psychology at the Mayo Clinic in Rochester, Minn., says he does such testing "very regularly," especially with children (who are particularly vulnerable to drug side effects) and patients with a personal or family history of adverse drug reactions. Many other doctors in his field are unfamiliar with the tests or don't use them.
To understand how these tests work, it helps to know something about the role of both the liver and genes in drug metabolism.
The liver is responsible for regulating most chemical levels in the blood. When you swallow a pill, the medication typically travels via the bloodstream from your stomach to your liver. There, one or more types of liver enzyme process the drug, breaking it down into forms that are easier for the rest of the body to use. Some of the drug travels on through your bloodstream; the rest is tagged as poisonous and filtered out.
The most important liver enzymes in drug metabolism are the ones in the "cytochrome P450" (CYP) family. They process 25 percent of all drugs, including those that cause the most adverse reactions -- antidepressants, anti-psychotics, painkillers, beta blockers (which slow the heart rate and lower blood pressure) and drugs used to treat attention-deficit hyperactivity disorder (ADHD).
Say you take a drug that is mostly processed by the enzyme CYP 2D6. If your liver produces too much of this enzyme, it could over-process the drug and flush it right out of your body, and you'd get no therapeutic effect. If, on the other hand, your liver produces too little of the 2D6 enzyme or none at all, the drug wouldn't be sufficiently broken down. Instead, it would build up in your bloodstream. You could overdose on what, for most people, would be a normal dose.
The Role of DNA
Just as eye color and hair color are determined by our genes, so are liver enzymes. And some vary more than others. There are more than 50 variations in the 2D6 gene. And the enzyme it governs is involved in metabolizing about 70 different drugs, including the antidepressants Paxil and Prozac and the ADHD drug Strattera, explains Mrazek. Even the popular antihistamine Claritin is metabolized by 2D6.
Like other genes, those that code for liver enzymes can vary by race and even your ancestors' geographic origin. Most people have two good copies of the 2D6 gene, so they produce a normal amount of the related liver enzyme. But an estimated 7 percent of Caucasians have two bad copies of the gene -- or no copies at all. These "poor metabolizers" don't produce any of the enzyme.
Sometimes, what you don't know can kill you. A 2000 case report in the Journal of Child and Adolescent Psychopharmacology tells of a 9-year-old boy with Tourette's syndrome, ADHD and obsessive-compulsive disorder who was treated with a combination of Ritalin, clonidine and Prozac. After 10 months on the drug regimen, he suffered seizures, then a heart attack; he later died. When an autopsy revealed toxic levels of Prozac in the child's blood and brain tissue, authorities first thought his adoptive parents had poisoned him. They were cleared when tests showed the boy was a 2D6 poor metabolizer.
Thirty percent of people who can trace their roots to North Africa and 20 percent of those whose families came from the Middle East have a different problem with 2D6: They are born with three or more copies of the gene. These "ultra-rapid metabolizers" produce too many 2D6 enzymes, which speed certain drugs out of the body. African Americans are more likely to be ultra-rapid metabolizers than whites, says Mrazek. Only 2 percent of Caucasians fall in this category.
