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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01RR000104-03
Application #
2460705
Study Section
Special Emphasis Panel (CM)
Project Start
1995-08-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Tufts University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Krishnaswamy, S; Duan, S X; Von Moltke, L L et al. (2003) Serotonin (5-hydroxytryptamine) glucuronidation in vitro: assay development, human liver microsome activities and species differences. Xenobiotica 33:169-80
Krishnaswamy, Soundararajan; Duan, Su X; Von Moltke, Lisa L et al. (2003) Validation of serotonin (5-hydroxtryptamine) as an in vitro substrate probe for human UDP-glucuronosyltransferase (UGT) 1A6. Drug Metab Dispos 31:133-9
Court, Michael H; Freeman, Lisa M (2002) Identification and concentration of soy isoflavones in commercial cat foods. Am J Vet Res 63:181-5
Court, M H; Duan, S X; von Moltke, L L et al. (2001) Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 299:998-1006
Court, M H (2001) Acetaminophen UDP-glucuronosyltransferase in ferrets: species and gender differences, and sequence analysis of ferret UGT1A6. J Vet Pharmacol Ther 24:415-22
Court, M H; Duan, S X; Hesse, L M et al. (2001) Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology 94:110-9
Court, M H; Greenblatt, D J (2000) Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms. Pharmacogenetics 10:355-69
Ilkiw, J E (1999) Balanced anesthetic techniques in dogs and cats. Clin Tech Small Anim Pract 14:27-37
Court, M H; Hay-Kraus, B L; Hill, D W et al. (1999) Propofol hydroxylation by dog liver microsomes: assay development and dog breed differences. Drug Metab Dispos 27:1293-9
Court, M H; Von Moltke, L L; Shader, R I et al. (1997) Biotransformation of chlorzoxazone by hepatic microsomes from humans and ten other mammalian species. Biopharm Drug Dispos 18:213-26

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