Inhibition of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin depends on protein biosynthesis.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic persistent organic pollutant. 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 and protein expression. 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 promotes tumor growth by preventing initiated cells from correctly executing apoptosis. In this study, we examined the effects of TCDD on apoptosis induced by UV-C light, ochratoxin A (OTA), and cycloheximide (CHX) in primary rat hepatocytes. Both UV-C light and OTA caused caspase activation and nuclear apoptotic effects. CHX did not activate caspases but nevertheless caused DNA fragmentation and chromatin condensation. TCDD inhibited UV-C light-induced apoptosis and this effect seemed to be dependent on AhR-activation as was shown by employing an AhR antagonist. In contrast to UV-C light-induced apoptosis, TCDD failed to protect primary rat hepatocytes from OTA- or CHX-induced apoptosis. Since both of these compounds inhibit protein biosynthesis as was demonstrated by measuring the incorporation of radiolabeled leucin and protein expression of cytochrome P450 1A1, we propose that the inhibition of apoptosis by TCDD depends on protein biosynthesis. Either TCDD induces some anti-apoptotic protein in an AhR-dependent manner or inhibits pro-apoptotic proteins induced by UV irradiation.
Chopra
Martin
M
Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.
Gährs
Maike
M
Haben
Melina
M
Michels
Christine
C
Schrenk
Dieter
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003513:Cycloheximide / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D007211:Indoles / Q000378:metabolism; D008297:Male; D009793:Ochratoxins / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000528:radiation effects; D051381:Rats; D017208:Rats, Wistar; D014466:Ultraviolet Rays
D007211:Indoles; D009793:Ochratoxins; D000072317:Polychlorinated Dibenzodioxins; C025589:ochratoxin A; C007293:DAPI; D003513:Cycloheximide; D019363:Cytochrome P-450 CYP1A1; D020169:Caspases