Abstract

This proposal is a request for salary support through a Research Career Development Award for Garold S. Yost. The award would allow Dr. Yost to spend full time in research of mechanisms of pneumotoxicity of xenobiotics. Prior work in Dr. Yost's laboratory included the mechanisms of bioactivation and organ and species selectivity of the pneumotoxin 3- methylindole (3MI). An RCDA would allow Dr. Yost to study selective toxicity to pulmonary tissues of several known pneumotoxins, such as 3MI, 2-methylnaphthalene, and butylated hydroxytoluene, and to extend his studies to other alkyl substituted aromatic compounds. these studies may permit predictions of the structural features of compounds that may be pneumotoxic and lead to an understanding of the precise biochemical, cellular, and physiological bases for the selective damage by these xenobiotics to lung tissue. The research will utilize a number of chemical, biochemical, cellula, isolated organ and whole animal techniques to evaluate the mechanisms whereby a series of pneumotoxins are bioactivated to toxic intermediates and/or detoxified by metabolic process involved in organ-selective pneumotoxicity and will lead to a better understanding of the risks involved in exposure of animals, including humans to these toxicants.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL002119-04
Application #
3074299
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Skordos, K W; Skiles, G L; Laycock, J D et al. (1998) Evidence supporting the formation of 2,3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole. Chem Res Toxicol 11:741-9
Skiles, G L; Yost, G S (1996) Mechanistic studies on the cytochrome P450-catalyzed dehydrogenation of 3-methylindole. Chem Res Toxicol 9:291-7
Thornton-Manning, J; Appleton, M L; Gonzalez, F J et al. (1996) Metabolism of 3-methylindole by vaccinia-expressed P450 enzymes: correlation of 3-methyleneindolenine formation and protein-binding. J Pharmacol Exp Ther 276:21-9
Smith, D J; Appleton, M L; Carlson, J R et al. (1996) Identification of beta-glucuronidase-resistant diastereomeric glucuronides of 3-hydroxy-3-methyloxindole formed during 3-methylindole metabolism in goats. Drug Metab Dispos 24:119-25
Ramakanth, S; Thornton-Manning, J R; Wang, H et al. (1994) Correlation between pulmonary cytochrome P450 transcripts and the organ-selective pneumotoxicity of 3-methylindole. Toxicol Lett 71:77-85
Smith, D J; Skiles, G L; Appleton, M L et al. (1993) Identification of goat and mouse urinary metabolites of the pneumotoxin, 3-methylindole. Xenobiotica 23:1025-44
Thornton-Manning, J R; Nichols, W K; Manning, B W et al. (1993) Metabolism and bioactivation of 3-methylindole by Clara cells, alveolar macrophages, and subcellular fractions from rabbit lungs. Toxicol Appl Pharmacol 122:182-90
Swaffar, D S; Harker, W G; Pomerantz, S C et al. (1992) Isolation, purification, and characterization of two new chemical decomposition products of methylazoxyprocarbazine. Drug Metab Dispos 20:632-42
Nichols, W K; Covington, M O; Seiders, C D et al. (1992) Bioactivation of halogenated hydrocarbons by rabbit pulmonary cells. Pharmacol Toxicol 71:335-9
Swaffar, D S; Pomerantz, S C; Harker, W G et al. (1992) Non-enzymatic activation of procarbazine to active cytotoxic species. Oncol Res 4:49-58

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