Abstract

The research proposal in this application is based on a problem for which the applicant has been the intellectual force: the influence of dietary lipids on the metabolism of xenobiotics. This area is important because health or disease often reflects the balance between reactions that convert non-toxic substances to toxic ones versus reactions that detoxify proximate toxins. Impairment of a major pathway of elimination, such as glucuronidation, could lead to acute disease (drug toxicity) or chronic disease (neoplasia). Treatment with a lipid composition of the microsomal membrane. The specific research to be pursued in the next 5 years pertains to how the lipid content and composition of oral and intravenous diets modulate the function of GT. Aside from demonstrating the effects of diet on the activity of GT in rat microsomes, it will be important to determine how these diet-dependent changes are produced. The extent to which changes in enzyme activity reflect altered amounts of enzyme and/or changes in the functional state of the enzyme will be determined. The effects of dietary lipids on acetaminophen glucuronidation in rats will be measured to show that diet-dependent changes in the functional state/amount of GT have an impact on the rate and pathways of metabolism of a therapeutic agent.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK001992-03
Application #
3080910
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Nanji, A A; Yang, E K; Fogt, F et al. (1996) Medium chain triglycerides and vitamin E reduce the severity of established experimental alcoholic liver disease. J Pharmacol Exp Ther 277:1694-700
Yang, E K; Kashfi, K; Chowdhury, J R et al. (1995) Phenolic antioxidants induce UDP-glucuronosyltransferase in rat liver. Ann N Y Acad Sci 768:231-6
Nanji, A A; Sadrzadeh, S M; Yang, E K et al. (1995) Dietary saturated fatty acids: a novel treatment for alcoholic liver disease. Gastroenterology 109:547-54
Catania, V A; Dannenberg, A J; Luquita, M G et al. (1995) Gender-related differences in the amount and functional state of rat liver UDP-glucuronosyltransferase. Biochem Pharmacol 50:509-14
Kashfi, K; Dannenberg, A J (1995) Omeprazole coinduces multiple xenobiotic-metabolizing enzymes in the rat. Ann N Y Acad Sci 768:237-42
Kashfi, K; McDougall, C J; Dannenberg, A J (1995) Comparative effects of omeprazole on xenobiotic metabolizing enzymes in the rat and human. Clin Pharmacol Ther 58:625-30
Kashfi, K; Rimarachin, J A; Weksler, B B et al. (1994) Differential induction of glutathione S-transferase in rat aorta versus liver. Biochem Pharmacol 47:1903-7
Dannenberg, A J; Reidenberg, M M (1994) Dietary fatty acids are also drugs. Clin Pharmacol Ther 55:5-9
Nanji, A A; Zhao, S; Lamb, R G et al. (1994) Changes in cytochromes P-450, 2E1, 2B1, and 4A, and phospholipases A and C in the intragastric feeding rat model for alcoholic liver disease: relationship to dietary fats and pathologic liver injury. Alcohol Clin Exp Res 18:902-8
Nanji, A A; Zhao, S; Sadrzadeh, S M et al. (1994) Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol Clin Exp Res 18:1280-5

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