May 8, 2009 - Research

Genetic Variation In Immune System Protein May Mediate Adverse Reactions To Acetaminophen

Even the safest drugs can be dangerous for some people.

Acetaminophen (Tylenol ®), for example, is responsible for more than a third of the approximately 2000 cases of acute liver failure that occur each year in the United States.   An estimated 10% of the patients experiencing liver failure due to acetaminophen were taking the recommended dose.   Even among people who do not have liver failure in response to acetaminophen, about a third show temporarily increased liver enzyme levels, a sign of toxicity.

A team of researchers led by David Threadgill at North Carolina State University has used a two-stage approach, which starts in mice and then moves to humans, to investigate whether genetics play a part in determining who will suffer from acetaminophen liver toxicity.   Their results, published online this week in the journal Genome Research, suggest that variations in the immune system may be important.

The researchers fed acetaminophen to several genetically distinct strains of mice and found that some had elevated levels of a liver enzyme called ALT, while others were unaffected.   Genetic mapping in these mice revealed several variations that could be responsible for these differences.

The researchers then looked at equivalent variations in human volunteers taking acetaminophen for seven days.   They found an association between a SNP in the CD44 gene and ALT levels: having one copy of a T and one copy of a C at this SNP led to higher ALT levels than having two Cs.

“One of the fascinating things that came out of this study was that the genetic variation in acetaminophen toxicity is not what all the toxicologists would have predicted in the first place.   CD44 doesn’t have anything to do with the rate of metabolism of the drug, but it does have something to do with the immune system,” said Ken Paigen, an executive research fellow at the Jackson Laboratory and a study co-author, in a statement.

There are limits on the interpretation of this study, however. The one person out of the 121 studied who had two Ts at actually had lower ALT levels after taking acetaminophen than people with either CT or CC at this SNP.   This person could be just an anomaly, but more research on this rare genotype will be needed.   Also, the researchers measured only modest elevations in ALT levels in response to normal doses of acetaminophen. Additional studies will be needed to understand if genetic predisposition to these small increases can predict which individuals are more susceptible to the more severe toxicity seen in overdose situations.

According to Threadgill, the success of his two-stage approach has broad implications for drug testing in general.   Genetic variations in humans have not traditionally been taken into account during pre-clinical drug testing in animals.

“If genetic differences are included in early safety testing, more accurate predictions of clinical response will be obtained.   The end result will be safer drugs,” Threadgill said in a statement.

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