Inhibition of UV-C light-induced apoptosis in liver cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic pollutant ubiquitously present in the environment. Most of the toxic effects of TCDD are believed to be mediated by high-affinity binding to the aryl hydrocarbon receptor (AhR) and subsequent effects on gene transcription. TCDD causes cancer in multiple tissues in different animal species and is classified as a class 1 human carcinogen. In initiation-promotion studies TCDD was shown to be a potent liver tumor promotor. Among other theories it has been hypothesized that TCDD acts as a tumor promotor by preventing initiated cells from undergoing apoptosis. We examined the effects of TCDD on ultraviolet C (UV-C) light-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells. TCDD inhibits UV-C light-induced apoptosis in both cell types. This effect is seen with chromatin condensation and fragmentation and appears to be mediated by the AhR in rat hepatocytes. Apoptosis induced by UV-C light in these cells is caspase-dependent and is accompanied by alterations in apoptosis-related gene expression such as up-regulation of proapoptotic bcl-2 family genes like bak and bax, and a marked down regulation of the expression of the antiapoptotic bcl-2. TCDD treatment of irradiated hepatocytes induces the expression of some apoptosis-related genes (birc3, dad1, pycard, tnf). Upstream apoptotic events, namely caspase activation and caspase substrate cleavage are not inhibited by TCDD treatment. We hypothesize that TCDD inhibits late-stage apoptotic events that lead to internucleosomal DNA fragmentation, maintaining chromosomal integrity probably in order to sustain metabolic capacity and hepatic elimination of substrates despite of an initiation of apoptosis.
Chopra
Martin
M
Institute of Food Chemistry and Toxicology, University of Kaiserslautern, 67663 Kaiserslautern, Germany.
Dharmarajan
Arunasalam M
AM
Meiss
Gregor
G
Schrenk
Dieter
D
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002843:Chromatin / Q000187:drug effects / Q000528:radiation effects; D004396:Coloring Agents; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D053938:DNA Fragmentation; D003851:Deoxyribonucleases / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000528:radiation effects; D008099:Liver / Q000166:cytology*; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays
D002843:Chromatin; D004396:Coloring Agents; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D019363:Cytochrome P-450 CYP1A1; D011065:Poly(ADP-ribose) Polymerases; D003851:Deoxyribonucleases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases