Joseph K. Ritter, Ph.D.
Hermes A. Kontos Medical Sciences Building, Room 531
1217 East Marshall Street
Richmond, Virginia 23298-0613
Phone: (804) 828-1022
Fax: (804) 828-0676
- University of Utah, 1987
- 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 understand better 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 chemo-preventive agents will facilitate studies of the basic mechanism of chemo-protection 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.
Fallon JK, Harbourt DE, Maleki SH, Kessler FK, Ritter JK and Smith PC. (2008) Absolute quantification of human uridine-diphosphate glucuronosyl transferase (UGT) enzyme isoforms 1A1 and 1A6 by tandem LC-MS. Drug Metabolism Letters. 2(3):210-22.
Stern ST, Tallman MN, Miles KK, Ritter JK and Smith PC. (2008) Androgen regulation of renal uridine diphosphoglucuronosyltransferase 1A1 in rats. Drug Metabolism and Disposition. 36(9):1737-9.
Falkner KC, Ritter JK and Prough RA. (2008) Regulation of the rat UGT1A6 by glucocorticoids involves a cryptic glucocorticoid response element. Drug Metabolism and Disposition. 36(2):409-17.
Gabra BH, Kessler FK, Ritter JK, Dewey WL and Smith FL. (2007) Decrease in N-methyl-D-aspartic acid receptor-NR2B subunit levels by intrathecal short-hairpin RNA blocks group I metabotropic glutamate receptor-mediated hyperalgesia. Journal of Pharmacology and Experimental Therapeutics. 322(1):186-94.