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Study Links CYP450 with Acetaminophen-Related Liver Damage in Children

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SANTORINI, Greece — Leslie Sheffield, of the Murdoch Children’s Research Institute at the Royal Children’s Hospital in Melbourne, Australia won the third annual meeting of the International Society of Pharmacogenomics poster contest with research on the genetics of adverse reaction to acetaminophen.

The study, supported by GlaxoSmithKline, associates CYP450 alleles with liver toxicity in 95 children who were given typical doses of acetaminophen for post-surgery pain relief. “None of the children in the study actually had liver failure, but they have the signs of early damage,” said Sheffield.

In particular, Sheffield found a CYP1A2*1F form of the gene to be linked to early liver damage. Sheffield suggested that the information could be used to stratify patients based on genotype, and doses could be adjusted to better reflect the metabolisms. Other meeting attendees Sheffield spoke with in Santorini will probably collaborate in developing the most appropriate genetic test for the gene’s different alleles.

Acetaminophen is often used in children because it is safer and more efficacious than aspirin, and the risk of toxic reactions seems to be lower in children than in adults, according to an article in the October 2001 issue of the journal Pediatrics.

Sheffield tested the three forms of CYP450 known to be involved in metabolizing acetaminophen to N-acetyl-p-benzoquinone imine — or NAPQI — a toxic metabolite. Typically, 80 to 90 percent of acetaminophen is converted to nontoxic sulfonide and gluconide, while the amount remaining is converted to NAPQI, which is “mopped up” by glutathione, said Sheffield. In patients with CYP1A2 mutations, the enzyme functions more efficiently than normal, converting acetaminophen to NAPQI more quickly than the clean-up mechanism remove it, and liver damage accumulates as a result, he added.

To measure early liver damage, Sheffield tested serum concentrations of hepatic transaminases and 3-cys-A adducts, which appear in laboratory animals given toxic doses of acetaminophen. The two biomarkers are “highly specific” biomarkers of the drug’s toxicity, according to Sheffield’s conference abstract.

In the study, patients with a high aspartate aminotransferase level represented 16 of a group of 82, all of whom had allele A of CYP1A2*1F. All 20 of 83 patients with a high level of 3-cys-A also had allele A of the gene. No patients having allele C were found to have either biomarker. Sheffield estimated the risk of occult liver damage for AA homozygous patients at 33 percent, while those having CC or AC he deemed “highly protective.”

— CW

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