A Medical College of Wisconsin study provides the strongest and most complete evidence to date of major changes occurring during human development in the types and levels of enzymes responsible for the disposition of drugs and environmental chemicals.
These enzymes can inactivate drugs, activate them, or do both, depending on the compound and the number of enzymes involved. Similarly, some environmental toxicants are inactivated and some are activated, depending on the chemistry of the compound, and sometimes, the dose. Overall, they enhance the ability of the body to eliminate these compounds.
The study was led by Ronald N. Hines, Ph.D.*, professor of pediatrics and of pharmacology and toxicology, and associate director of the Children's Research Institute, Children's Hospital and Health System. Children's Hospital is a major teaching affiliate of the Medical College.
The research, to be presented at the American Association for the Advancement of Science annual meeting, Feb. 16, in St. Louis, concludes that application of this and similar information could help predict an individual child's likelihood of effective drug treatment or susceptibility to an unfavorable drug reaction.
The study found that some enzymes known to share regulatory mechanisms in adults appear to employ different regulatory mechanisms during development. The investigators also found a period of higher than normal variability for several enzymes in the three-to-six months after birth, suggesting that the onset or increased expression of these enzymes can vary considerably among individual children during that period.
"The dramatic changes observed in enzyme expression must be considered when examining issues of drug effectiveness and safety during early life stages," says Dr. Hines. "Additional studies are needed to understand how these dramatic changes are regulated, and the molecular basis for differences among individuals, to better predict drug and toxicant responses in children."
To date, data has been obtained on fourteen enzymes crucial to drug or toxicant disposition. Among their key findings are:
Other members of the team included researchers from the Medical College departments of pediatrics, and pharmacology and toxicology; the University of Arizona, Tucson; Wayne State University, Detroit; the University of Washington, Seattle and Pfizer in St. Louis. The study was funded in part by grants from the National Cancer Institute, the National Institute of Environmental Health Sciences, and the National Institute of General Medicine.
Dr. Hines is also co-section chief of clinical pharmacology, pharmacogenetics and teratology at the Medical College of Wisconsin. His research efforts have focused on understanding mechanisms of gene regulation, particularly in response to environmental toxicant or drug exposure, and how inter-individual differences in gene expression might impact disease susceptibility. More recently, he also has turned his attention toward understanding how differences in gene expression during development impact the risk for life-stage-dependent toxicity, including adverse drug reactions. He has over 97 publications in the peer reviewed literature on his research findings in these areas.
Materials provided by Medical College of Wisconsin. Note: Content may be edited for style and length.
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