The proposed research will use biochemical and molecular genetic techniques to elucidate commonly known, but poorly understood, defects in drug metabolism that are characteristic of particular species, breeds and strains of laboratory animals. The primary focus of this project is on glucuronidation. This knowledge is important to human health not only from the aspect that it will improve the predictability of the effects of drugs in animal models of human disease, such as the cat, and perhaps in preclinical pharmaceutical testing, but also because such animals may model similar molecular bases for drug glucuronidation deficiency in certain patients. Clinically, abnormalities in glucoronidation accounts in part for significantly enhanced toxicity of acetaminophen [Tylenol(R)] and acetylsalicylic acid (aspirin) in the cat compared with other species. Similar glucuronidation deficits have been observed in human patients with Crigler-Najjar syndrome and Gilbert's syndrome (a disease that is estimated to affect 5-7% of the population). In support of this research focus, preliminary data from this laboratory suggests that the cat lacks significant expression of one isoform of UDP- glucuronyltransferase shown to be defective in Crigler-Najjar syndrome and possibly Gilbert's syndrome.
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