Sustained Increase in Intracellular Free Calcium and Activation of Cyclooxygenase-2 Expression in Mouse Hepatoma Cells Treated with Dioxin

• Published in: Biochemical pharmacology Vol. 54; no. 12; pp. 1287 - 1296
• Main Authors: Puga, Alvaro, Hoffer, Amy, Zhou, Shaoying, Bohm, Jeanne M, Leikauf, George D, Shertzer, Howard G
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.12.1997; Elsevier Science
• Subjects: Animals; arachidonic acid; Arachidonic Acid - metabolism; Biological and medical sciences; Calcium - metabolism; calcium homeostasis; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Cyclooxygenase 1; dioxin; Enzyme Induction - drug effects; Gastroenterology. Liver. Pancreas. Abdomen; Homeostasis - drug effects; Isoenzymes - biosynthesis; Isoenzymes - drug effects; Liver Neoplasms, Experimental - enzymology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Membrane Proteins; Mice; Polychlorinated Dibenzodioxins - toxicity; prostaglandin synthase; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - drug effects; RNA, Messenger - analysis; Tumor Cells, Cultured; Tumors; prostaglandin synthase; arachidonic acid; calcium homeostasis; dioxin; Prostaglandin-endoperoxide synthase; Enzyme; Gene product; Toxicity; Liver; Rodentia; Hepatic disease; Malignant tumor; Arachidonic acid; Gene expression; In vitro; Vertebrata; Mammalia; Calcium ion; Mouse; Animal; Established cell line; Digestive diseases; Oxidoreductases; Tumor cell
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00417-6

2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) is a non-genotoxic environmental pollutant that causes multiple adverse effects in experimental animals and in humans. We show here that TCDD treatment of mouse hepatoma cells causes a rapid mobilization of intracellular calcium both in wild type Hepa-1 cells and in its c2 variant, a cell line that has highly reduced levels of functional aromatic hydrocarbon (Ah) receptor (AHR). In wild type cells, but not in the c2 variant, TCDD treatment leads to a sustained elevation of cytosolic free calcium. TCDD also induces elevated levels of cyclooxygenase-2 (COX-2) mRNA in wild type and in c37, a CYP1A1-deficient cell line, but not in c2 cells. Induction of Cox-2 is in fact dependent on the presence of a functional Ah receptor, since it can be blocked by antisense oligonucleotides to Ah receptor mRNA. Most likely as a consequence of Cox-2 induction, we find a significant increase in the level of 12-hydroxyheptadecatrienoic acid (12-HHT) secreted from TCDD-treated Hepa-1 cells. In addition, we observe elevated levels of 6-keto prostaglandin F 1α in c2 cells and high levels of secreted prostaglandin F 2α in c2, c37 and c4, the variant cell line lacking aromatic hydrocarbon nuclear translocator protein. These data suggest that Cox-2 activation by TCDD leads to the release of prostaglandins, eicosanoids and other mediators which may have an important role in the biological and toxic effects of TCDD.