Differential Effects of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the Expression of Prostaglandin-H Synthase Isoenzymes in Mouse Tissues

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds cause a number of toxic responses including wasting syndrome, thymus atrophy and immunotoxicity, reproductive and developmental toxicity, dermal toxicity, hyperplasias, and carcinogenesis. Most if not all toxic effects of TCDD have been found to be mediated by the arylhydrocarbon receptor (AhR) to which TCDD binds with high affinity. The TCDD: AhR complex is known to translocate into the nucleus where it dimerizes with ARNT, the socalled AhR nuclear translocator protein. This complex can bind to dioxin responsive elements (DREs) located in the regulatory region of several TCDD-sensitive genes and leads to activation of their transcription (rev. in Landers and Bunce, 1991). This has been well shown for several phase 1 and phase 2 enzymes, for example cytochrom P450 1A1 (CYP1A1) and glutathione S-transferase Ya (Gonzalez et al., 1985; Pimental et al., 1993). Recently two DRE motifs were identified in the regulatory region of the mouse prostaglandin endoperoxide H synthase-2 (PGHS-2) gene (Kraemer et al., 1996); this raised the question whether PGHS-2 is induceable by TCDD.