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:
- The dominant oxidative enzyme, CYP3A4, and the expression levels of other oxidative enzymes in the CYP and FMO gene families, are very different in adults than in infancy, and vary considerably during each trimester of gestation.
- By the time a child reaches one or two years of age, they have only 20 to 50 percent of the adult CYP3A4 value, with evidence suggesting a gradual increase to adult values by age 18. In contrast, nearly 50% of children have near adult levels of CYP2C9, considered by many to be the second most important oxidative enzyme, at or near birth.
- Of the conjugating enzymes studied (all members of the SULT gene family). SULT2A1 is low or absent during the first trimester of gestation, is highly variable in the first four months of life, and increases gradually to adult values by age one.
- In contrast, SULT1A1 is constant throughout fetal development with no postnatal changes, while SULT1E1 levels are highest during the first trimester (five times the median adult level), and decline steadily through gestation and after birth.
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.