Abstract

Objectives: Elucidation of mechanisms regulating the hepatobiliary fate of chemical carcinogens and other xenobiotics.
Specific Aims : (1) Investigate the role of glutathione (GSH) in the metabolism and biliary excretion of N, N-dimethyl-4-aminoazobenzene (DAB). (2) Identify and characterize cytosolic factors which affect microsomal metabolism of DAB. Methods: (1) Hepatic GSH levels are altered by treating rats with depleting agents and effects are determined on DAB metabolism, lipid peroxidation and heme oxygenase. Correlations between the effects will be drawn. (2) Standard methods of purification will be used to isolate cytosolic protein(s) which affect P-450-catalyzed metabolism of DAB. The mechanism of the interaction will be investigated by studying the kinetics of DAB metabolism. Health-Related Aspects of Project: Metabolism of xenobiotics may involve activation or detoxication. GSH is a major factor in determining the fate of many xenobiotics and its hepatic level varies with diet and exposure to environmental pollutants. Therefore, understanding GSH control of xenobiotic metabolism provides insight into the potential toxicity of many foreign compounds.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA014231-12
Application #
3163895
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1983-06-01
Project End
1986-06-30
Budget Start
1985-06-01
Budget End
1986-06-30
Support Year
12
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Zbaida, S; Brewer, C F; Levine, W G (1994) Hepatic microsomal azoreductase activity. Reactivity of azo dye substrates is determined by their electron densities and redox potentials. Drug Metab Dispos 22:412-8
Zbaida, S; Levine, W G (1992) Role of electronic factors in binding and reduction of azo dyes by hepatic microsomes. J Pharmacol Exp Ther 260:554-61
Stoddart, A M; Levine, W G (1992) Azoreductase activity by purified rabbit liver aldehyde oxidase. Biochem Pharmacol 43:2227-35
Levine, W G; Stoddart, A; Zbaida, S (1992) Multiple mechanisms in hepatic microsomal azoreduction. Xenobiotica 22:1111-20
Levine, W G (1991) Metabolism of azo dyes: implication for detoxication and activation. Drug Metab Rev 23:253-309
Zbaida, S; Levine, W G (1991) A novel application of cyclic voltammetry for direct investigation of metabolic intermediates in microsomal azo reduction. Chem Res Toxicol 4:82-8
Zbaida, S; Levine, W G (1990) Characteristics of two classes of azo dye reductase activity associated with rat liver microsomal cytochrome P450. Biochem Pharmacol 40:2415-23
Stoddart, A M; Levine, W G (1990) Azoreduction of dimethylaminoazobenzene (DAB) in primary cultures of rat hepatocytes. Effect of hypolipidemic agents. Drug Metab Dispos 18:36-41
Zbaida, S; Stoddart, A M; Levine, W G (1989) Studies on the mechanism of reduction of azo dye carcinogens by rat liver microsomal cytochrome P-450. Chem Biol Interact 69:61-71
Levine, W G; Raza, H (1988) Mechanism of azoreduction of dimethylaminoazobenzene by rat liver NADPH-cytochrome P-450 reductase and partially purified cytochrome P-450. Oxygen and carbon monoxide sensitivity and stimulation by FAD and FMN. Drug Metab Dispos 16:441-8

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