Project: Research project

Project Details


This program-project grant seeks and enhanced understanding of
the nature of the carcinogenic processes induced by chemicals.
Three of the projects are directed primarily toward a better
understanding of events related to the initiation of tumors by
chemicals, two will provide a better understanding of the post-
initiation stages of carcinogenesis, and the sixth has implications
for both the initiation and post-initiation stages. The studies in
the Millers' laboratory are directed particularly toward the
identification of the electrophilic metabolites of chemical
carcinogens that are of major importance to specific carcinogenic
process and to the characterization of the reaction products of
these metabolites with cellular macromolecules, especially DNA.
Dr. Kasper's studies will provide a better biochemical
understanding of the structures of the cytochromes P-450,
NADPH-cytochrome P-450 oxidoreductase, and epoxide hydrolase
and of the regulation of their activities in vivo at both the
transcriptional and translational levels. These data are of great
importance in view of the involvement of these enzymes in the
activation and/or deactivation of a wide variety of chemical
carcinogens. Dr. Fahl's research seeks a detailed understanding
of the role of glutathione S-transferase-catalyzed reactions in
reducing the effective levels of electrophiles formed from
carcinogens in target cells and in thereby decreasing the
susceptibility of the cells to mutagenesis or carcinogenesis. Dr
Drinkwater is exploring genetic factors that predispose mice to
the development of gross hepatomas through enhancing the rate
of growth of microscopic foci of enzyme-altered cells and/or
hepatomas. Dr. Pitot will analyze sequential changes in enzyme-
altered hepatocytes during the progression stage of rat
hepatocarcinogenesis. He will also study the regulation of
transcription and the stability of specific mRNAs in hepatocytes.
Dr. Poland will search for variants of the Ah receptor in human
lymphoblastoid cell lines and examine the functional significance
of these variants. This integrated research program will utilize
chemical, biochemical, molecular biological, and biological
approaches to develop a better understanding of chemical
StatusNot started