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The ontogeny of hepatic detoxification in children : implications for pediatric non-alcoholic fatty liver disease

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Item Summary

Title: The ontogeny of hepatic detoxification in children : implications for pediatric non-alcoholic fatty liver disease
Authors: Miyagi, Shogo John
Keywords: fatty liver disease
Issue Date: Aug 2011
Publisher: [Honolulu] : [University of Hawaii at Manoa], [August 2011]
Abstract: The research presented in this dissertation provides, for the first time, a description of the ontogeny of hepatic antioxidants in the pediatric liver as well as the ontogeny of hepatic detoxification in children. Herein, we have studied the entire hepatic antioxidant defense network (with the exception of nitric oxide synthase) as it develops throughout childhood. Results demonstrated highest hepatic antioxidant capacity in the neonate that declines throughout childhood to a nadir around the age of ten then subsequently rebounds to adult levels after adolescence. Children may be less protected between the ages of six and ten years of age due to decreased antioxidant status (Chapter 2). Additionally, the ontogenies of four different UDP-glucuronosyltransferase isoforms (UGTs 1A1, 1A4, 1A6, and 1A9) were examined. Experiments showed each enzyme were independently regulated, maturing at different rates and ages. In general, these enzymes showed full activity by two years of age. Interestingly, UGT1A1, 1A4 and 1A6 maturation may be regulated post-translationally and/or allosterically while UGT1A9 matures mostly due to transcriptional effects. When scaled to whole liver, hepatic clearances matured later, from one to eighteen years of age. Furthermore, the age of maturation varied between the four clearance models (well-stirred and parallel tube models using allometric pharmacokinetics versus physiology-based pharmacokinetics). The difference indicated that one model cannot be applied to every isoform and must be evaluated on a case-by-case basis (Chapters 3--5). Since clearance matures years after birth, children may be more susceptible to chemical toxicities and subsequent liver damage. Coupled together, these descriptions provide a general status of hepatic detoxification capacity. Lack of this capacity, due to environmental or genetic effects, may have implications in the role of some pediatric liver diseases, such as in pediatric non-alcoholic fatty liver disease (Chapter 6). Overall, these data presented herein have substantial value to the field of developmental pharmacology and pediatric pharmacokinetics, as well as potential reasons for drug toxicities, adverse drug reactions, and liver diseases in children.
Description: Ph.D. University of Hawaii at Manoa 2011.
Includes bibliographical references.
URI/DOI: http://hdl.handle.net/10125/101668
Appears in Collections:Ph.D. - Biomedical Sciences (Tropical Medicine)



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