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Childhood Changes in Metabolism Enzyme Expression Still Challenge for PGx to Predict

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Certain metabolic enzymes are differently regulated in children than in adults, a finding that has important implications for the prescription of certain drugs, according to research presented last week at the annual meeting of the American Association for the Advancement of Science in St. Louis.

Little is known about the expression levels of metabolism enzymes during different phases of childhood, and the practical lesson that can be learned for pharmacogenomic purposes is simply that "variability in the onset of expression is a function of development — it's a target area, basically," Ronald Hines, associate director of the Children's Research Institute at the Children's Hospital and Health System of the Medical College of Wisconsin, told Pharmacogenomics Reporter last week. "It's only been in the last couple of years that we've been able to document that this occurs." Hines is the author or co-author of several of the research articles he presented this week at the conference.

The three to six months after birth show inter-individual variability for several metabolism enzymes that is higher than thata found in adults, in addition to year-to-year changes. "With a lot of different enzyme systems … we have coined the term, 'window of hypervariability,'" said Hines. "So there are differences between individuals, as to when they turn the system on," he said.

But predicting the expression levels of particular metabolism enzymes, many of which are active in the liver, is difficult. "We're very interested in genetics, but you can have a poor-metabolizer phenotype that has nothing to do with genetics, per se," said Hines. "It's just a matter that the child, the neonate or infant hasn't turned on its enzyme system yet, and so they're poor metabolizers," he said. "They don't have a genetic defect — a year later, they'll be fine."

Whether gene expression of metabolism enzymes is itself genetically controlled "is an interesting question," Hines said. The activation of metabolism enzymes in early childhood "may be under genetic control, but we're just beginning to look at what might be responsible for that," he said. "I think it's probably either variation in the control regions of the gene, or variability in the transcription factors that are acting on those." Epigenetic factors might also help to explain differences in the expression levels of metabolism enzymes, said Hines.

Hines' group examined about 240 neonatal liver samples, with approximately 60 samples harvested during the first few months of a child's life. Until the group had been able to gather enough samples through the NICHD tissue banks to test for the expression levels of various enzymes, it had not been possible to know for sure whether age-related differences existed, Hines said.

Without understanding the mechanisms of regulation of these enzymes in different phases of human growth, clinicians must resort to the tools of the pre-genetic testing era. "There are probe drugs that we can use in children — you have to be very careful, obviously — but you can do the same thing," Hines said.

Hines said he was not aware of any diagnostic or pharmaceutical firms working on products targeted toward age-related metabolism-enzyme regulation. However, Hines said he and other investigators involved with the International Life Science Institute in Washington, DC, are attempting to build a database for modeling the kinetics of certain drugs based on what is currently known about CYP enzyme levels in childhood.

— Chris Womack ([email protected])

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