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University of Colorado Denver

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John A. Thompson, PhD

Professor Emeritus, Department of Pharmaceutical Sciences


Mailing address:

University of Colorado School of Pharmacy
Mail Stop C238
12850 E. Montview Blvd. V20-2107
Aurora, CO 80045

Office Location:

Pharmacy and Pharmaceutical Sciences Building (V20)
Second Floor
Room 2107

Lab Location:

Pharmacy and Pharmaceutical Sciences Building (V20)
Second Floor
Room 2430, 2440

Contact:

Affiliation:

  • Member, University of Colorado Cancer Center

Training and Education:

  • BA, Clark University (Chemistry)
  • PhD, University of California, Los Angeles (Organic Chemistry)

Research Interests:

Research in this laboratory involves elucidation of pathways involved in the metabolic activation of toxic chemicals and carcinogens, and identification of the cellular targets of such species. Our current focus is to determine underlying events responsible for cytotoxicity and tumor promotion by phenolic antioxidants. Two general types of reactive metabolites are formed during oxidation of alkylated phenols by cytochrome P450, electrophilic quinone methides and free radical-generating hydroperoxides. Both species damage proteins, the former through covalent binding to nucleophilic groups and the latter by oxidizing susceptible amino acid residues.

Quinone methides have been shown to induce the expression of genes related to cellular stress and cause the irreversible inhibition of protective enzymes. The hydroperoxide metabolites also inhibit enzyme activity by oxidizing critical residues. We utilize a variety of methods including liquid chromatography and electrospray tandem mass spectrometry to identify the affected proteins and specific sites of damage within these molecules.  The data provide a basis for elucidating mechanisms of toxicity and insight into strategies for eliminating such effects

Teaching:

  • Professional Program: Medicinal Chemistry, Metabolism

Representative Publications:

  • Lemercier, J.N., Meier, B., Gomez, J.D., and Thompson, J.A. (2004) Inhibition of glutathione S-transferase P1-1 in mouse lung epithelial cells by the tumor promoter 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone (BHT-quinone methide): protein adducts investigated by electrospray mass spectrometry. Chem. Res. Toxicol. 17, 1675-1683.
  • Meier B.W., Gomez, J.D., Zhou, A., and Thompson, J.A. (2005) Immunochemical and proteomic analysis of covalent adducts formed by quinone methide tumor promoters in mouse lung epithelial cell lines. Chem. Res. Toxicol. 18, 1575-1585.
  • Veluri, R., Singh, R.P., Liu, Z., Thompson, J.A., Agarwal, R., and Argarwal, C.  (2006) Fractionation of grape seed extract and identification of gallic acid as one of the major active consitutents causing growth inhibition and apoptotic death of DU145 hyman prostate carcinoma cells.  Carcinogenesis 27: 1445-1453.
  • Meier, B., Gomez, J. D., Kirichenko, O., and Thompson, J. A. (2007) Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes. Chem. Res. Toxicol., 20: 199-207.
  • Agarwal, C., Veluri, R., Kaur, M., Chou, S.-C., Thompson, J. A., and Agarwal, R. (2007) Fractionation of high molecular weight tannins in grape seed extract and identification of procyanidin B2-3,3¹-di-O-gallate as a major active constituent causing growth inhibition and apoptotic death of DU145 prostate carcinoma cells. Carcinogenesis, 28:1478-1484.

Keywords:

Carcinogenesis, bioactivation, mass spectrometry, drug metabolism, proteomics, toxicology