Abstract

Garlic constituents including diallyl sulfone (DAS02) have been identified as potential protective agents, but the basis for the effects ar poorly understood, especially in the lung, a tissue that is susceptible to chemically-induced toxicities and carinogenesis. The long-term objectives of this application are to (1) to determine the potential inhibitory effects of garlic constituents on pulmonary toxicity and carcinogenicity, and 92) to identify the mechanisms by which garlic constituents protect from these adverse effects. The proposed studies will use an in vivo murine model of lung tumorigenesis induced by the carbamate compounds, ethyl carbamate (EC) and vinyl carbamate (VC). In vitro studies will use microsomal preparations from the lungs of mice and humans.
The specific aims are as follows: 1) Investigate the potential inhibitory effects of DA802 on metabolism of EC and VC by cytochrome P450 CYP2EI. Lung microsomal incubation will be performed with EC or VC to determine the extent to which DAS02 inhibits carbamate metabolism. 2) Investigate the inhibitory effects of DAS02 on the formation of VC expoxide (VC0), the metabolite formed from EC and VC. The VC0 will be captured with glutathione (GSH) as the VC0-GSH conjugate in microsomal incubations. Incubation will also be performed with DAS02 or microsomes prepared from mice treated with garlic homogenates to determine the extent to which garlic constituents exert inhibitory effects. 3) Investigate the potential sex- related difference in formation of the VC0-GSH conjugate. Incubations will be performed with microsomes from male and female mice and humans. 4) Investigate the potential of DAS02 to inhibit the formation of carbamate-induced DNA adducts. 32_-postlabeling analyses will be used to identify the DNA adducts formed from exposure to EC or VC, and the extent to which DAS02 inhibits their formation. 5) Determine potential inhibition of lung tumors formed from the carbamates by garlic constituents. Mice will be treated with DAS02 or garlic homogenates before treatment with EC or VC, and the incidence and number of lung tumors generated determined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073220-03
Application #
2837724
Study Section
Special Emphasis Panel (SRC (02))
Program Officer
Whitted, Jacqueline
Project Start
1996-12-16
Project End
1999-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Queen's University at Kingston
Department
Type
DUNS #
City
Kingston
State
ON
Country
Canada
Zip Code
K7 3-N6

  Publications

Forkert, P G (2001) Mechanisms of 1,1-dichloroethylene-induced cytotoxicity in lung and liver. Drug Metab Rev 33:49-80
Forkert, P G; Premdas, P D; Bowers, R J (2000) Epoxide formation from diallyl sulfone is associated with CYP2E1 inactivation in murine and human lungs. Am J Respir Cell Mol Biol 23:687-95
Premdas, P D; Bowers, R J; Forkert, P G (2000) Inactivation of hepatic CYP2E1 by an epoxide of diallyl sulfone. J Pharmacol Exp Ther 293:1112-20
Forkert, P G (1999) In vivo formation and localization of 1,1-dichloroethylene epoxide in murine liver: identification of its glutathione conjugate 2-S-glutathionyl acetate. J Pharmacol Exp Ther 290:1299-306
Forkert, P G (1999) 1,1-Dichloroethylene-induced Clara cell damage is associated with in situ formation of the reactive epoxide. Immunohistochemical detection of its glutathione conjugate. Am J Respir Cell Mol Biol 20:1310-8
Dowsley, T F; Reid, K; Petsikas, D et al. (1999) Cytochrome P-450-dependent bioactivation of 1,1-dichloroethylene to a reactive epoxide in human lung and liver microsomes. J Pharmacol Exp Ther 289:641-8
Forkert, P G; Malkinson, A M; Rice, P et al. (1999) Diminished CYP2E1 expression and formation of 2-S-glutathionyl acetate, a glutathione conjugate derived from 1,1-dichloroethylene epoxide, in murine lung tumors. Drug Metab Dispos 27:68-73
Forkert, P G; D'Costa, D; El-Mestrah, M (1999) Expression and inducibility of alpha, pi, and Mu glutathione S-transferase protein and mRNA in murine lung. Am J Respir Cell Mol Biol 20:143-52
Lee, R P; Forkert, P G (1999) Inactivation of cytochrome P-450 (CYP2E1) and carboxylesterase (hydrolase A) enzymes by vinyl carbamate in murine pulmonary microsomes. Drug Metab Dispos 27:233-9
Lee, R P; Parkinson, A; Forkert, P G (1998) Isozyme-selective metabolism of ethyl carbamate by cytochrome P450 (CYP2E1) and carboxylesterase (hydrolase A) enzymes in murine liver microsomes. Drug Metab Dispos 26:60-5

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