Inhibition of apoptosis by 2378tetrachlorodibe

Authors: Martin Chopra Maike Gährs Melina Haben Christine Michels Dieter Schrenk

Publish Date: 2010/01/27

Volume: 26, Issue: 4, Pages: 391-401

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Abstract

2378Tetrachlorodibenzopdioxin TCDD is a highly toxic persistent organic pollutant Most of the toxic effects of TCDD are believed to be mediated by highaffinity 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 livertumor 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 UVC light ochratoxin A OTA and cycloheximide CHX in primary rat hepatocytes Both UVC 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 UVC lightinduced apoptosis and this effect seemed to be dependent on AhRactivation as was shown by employing an AhR antagonist In contrast to UVC lightinduced apoptosis TCDD failed to protect primary rat hepatocytes from OTA or CHXinduced 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 antiapoptotic protein in an AhRdependent manner or inhibits proapoptotic proteins induced by UV irradiation

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