2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that mediates a variety of biological effects including the induction of several xenobiotic metabolizing enzymes. The mechanism of induction of cytochrome P-450 1A1 (CYP1A1) gene is the best understood. Induction by TCDD occurs at the level of transcription and is mediated by the Ah receptor which interacts with TCDD, gains access to the nucleus, and associates with a nuclear protein termed Amt. The study described in this fellowship will examine the induction of class 3 aldehyde dehydrogenase (ALDH) by TCDD. The concentration of TCDD required to induce transcriptional activation of ALDH is 10--fold that needed to induce CYP1A1. The main goal of this project is to analyze the mechanism responsible for the differential responsiveness of CYP1A1 and ALDH. These studies may generate new insights into the factors that determine the severity of TCDD's health effects.
