CHARACTERIZATION OF A UGT FOR MORPHINE 6 GLUCURONIDE

Oregon Health And Science University, Portland OR

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Abstract

DESCRIPTION: (Applicant's Abstract) The long-term objective of the applicant is to become a physician-scientist with expertise in Neonatal Pharmacology. To achieve that goal she has assembled a team of mentors from the Departments of Physiology and Pharmacology and the Department of Pediatrics at Oregon Health Sciences University (OHSU) that consists of: a Pharmacologist with expertise in the drug abuse field and morphine metabolism; a Pediatrician skilled in the latest molecular and genetic techniques; a Pharmacologist who is an expert in protein chemistry and drug metabolism; and a Molecular Endocrinologist with over 20 years experience in molecular biology. In addition, OHSU provides a strong research environment in which the applicant can pursue her goals. The overall goal of the research project is to characterize a guinea pig UDP-glucuronosyltransferase (UGT) that metabolizes morphine to morphine-6-glucuronide, its active metabolite. This metabolite is produced by humans, guinea pigs and rabbits, but not by the more frequently-studied rat. There is considerable evidence that the UGT that produces morphine-6-glucuronide is different from those that produce the non-analgesic metabolite, morphine-3-glucuronide. The characterization will consist of purification of the protein, identification of the cDNA, and elucidation of the ontogeny and tissue distribution of this glucuronosyltransferase. The morphine-6-glucuronide produced by this transferase is a more potent analgesic and respiratory depressant than the parent morphine. It is, therefore, important in the drug abuse field to understand the tissue distribution and ontogeny of this glucuronosyltransferase. In the process of contributing to the understanding of morphine metabolism, the investigator will acquire a multidimensional education that will allow her to function as an independent investigator in neonatal pharmacology with expertise in both clinical and basic research.