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Joseph K. Ritter,
Ph.D. Associate professor 1217 East Marshall Street Hermes A. Kontos Medical Sciences Building P.O. Box 980613 Richmond, Virginia 23298-0613 Phone: (804) 828-1022 Fax: (804) 828-0676 E-mail: jritter@vcu.edu Publications: selected | PubMed Lab: Video: |
Education: University of Utah, 1987
Research interests:
Molecular toxicology; genetics and molecular biology of drug metabolizing enzymes; role of induction of Phase II enzymes in chemical carcinogenesis and chemoprevention
The research emphasis in this laboratory focuses on the molecular toxicology of Phase II detoxifying enzymes. Phase II enzymes such as the glutathione S-transferases and UDP-glucuronyl transferases detoxify toxic substances by catalyzing their conjugation with the water-soluble substances, glutathione and glucuronic acid, respectively. Conjugation reduces their biological reactivity and enhances their rate of excretion. Because carcinogens represent one of the most important classes of hazardous substances metabolized and detoxified by Phase II enzymes, our effort is directed at understanding the roles of Phase II enzymes in carcinogenesis and anticarcinogenesis. Our long-term goal is to better understand the Phase II enzymes as positive or negative risk factors influencing individual susceptibility to carcinogenesis.
The expression of genes encoding Phase II enzymes is known to be selectively and markedly increased by hundreds of agents (e.g. oltipraz, see below). Laboratory animals are protected from the cancer-causing effects of carcinogens when selected Phase II enzyme inducers are administered prior to chemical carcinogens. The potential use of Phase II enzyme inducers in humans for prevention of cancers related to exposure to carcinogens has prompted studies aimed at understanding their molecular effects. Our laboratory is utilizing biochemical and molecular biological research methodologies to identify and characterize the targets of selective Phase II enzyme inducers. The cloning of genes responding to cancer chemopreventive agents will facilitate studies of the basic mechanism of chemoprotection and provide insights about the relationship between gene regulation, enzyme polymorphism and carcinogen detoxification.
Currently we are studying the mechanism(s) by which oltipraz, a thiol compound under clinical development as a cancer-preventive agent, inhibits carcinogenesis and other toxicities caused by polycyclic aromatic hydrocarbons. Polycyclics are a class of suspected human carcinogens and widespread environmental contaminants. Intervention with oltipraz may have utility to prevent the consequences of long-term occupational, nutritional and environmental exposure to polycyclics.
Kessler, F. and Ritter, J.K.: Induction of rat liver benzo(a)pyrene -trans-7,8- dihydrodiol glucuronidating activity by oltipraz and b-naphthoflavone. Carcionogenesis 18: 107-114, 1997.
Grove, A.D., Kessler, F.K., Metz, R.P., and Ritter, J.K.: Cloning and expression of an oltipraz-inducible UDP-glucuronosyltransferase (UGT1A7) with activity towards benzo(a)pyrene-7,8-dihydrodiol. J. Biol. Chem. 272: 1621-1627, 1997.
Metz, R.P. and Ritter, J.K.: Transcriptional activation of the UDP-glucuronosyltransferase 1A7 gene in rat liver by aryl hydrocarbon receptor ligands and oltipraz. J. Biol. Chem. 273: 5607-5614, 1998.
Munzel, P.A., Lehmkoster, T., Bruck, M., Ritter, J.K. and Brock, K.W.: Aryl hydrocarbon receptor-inducible and constitutive expression of human UDP-glucuronosyltransferase UGT1A6. Arch. Biochem. Biophys. 350: 72-78, 1998.
Brock, K.W., Raschko, F.T., Gschaeidmeier, H.M., Seidel, A., Oesch, F., Grove, A.D. and Ritter, J.K.: Cooperation between two PAH-inducible UDP-glucuronosyltransferases (UGT1A6 and UGT1A7) in the formation of benzo(a)pyrene-3,6-diphenol diglucuronide. Biochem. Pharmacol. In press.