Adrenal Bioactivation and Toxicity of 3-MeSO2-DDE, o,p´-DDD and DMBA Investigated in Tissue Slice Culture

• Main Author: Lindhe, Örjan
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Uppsala universitet, Institutionen för evolutionsbiologi 2001
• Subjects: Developmental biology; adrenal cortex; 3-MeSO2-DDE; o; p´-DDD; DMBA; bioactivation; binding; toxic; Utvecklingsbiologi; atlantic cod
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1538

I developed a precision-cut adrenal slice culture procedure to investigate cytochrome P450 (CYP) catalysed irreversible binding and adrenocorticolytic effects in human, rodent, and fish adrenal tissue, ex vivo. Autoradiography and radioluminography of exposed tissue slices showed that the potent adrenal toxicant 3-methylsulphonyl-2,2´-bis(4-chlorophenyl)-1,1´-dichloroethene (MeSO2-DDE) causes a selective metabolite binding in zona fasciculata (ZF), which is diminished by the CYP11B1 inhibitor metyrapone. MeSO2-DDE also reduces corticosterone secretion, increases 11-deoxycorticosterone secretion and causes mitochondrial degeneration in ZF cells in cultured mouse adrenal slices. ACTH treatment of mice induces CYP11B1 and increases irreversible MeSO2-DDE binding and toxicity in ZF cells. Metyrapone-sensitive binding of MeSO2-DDE is also observed in human zona fasciculata/reticularis (ZF/ZR) and 11-deoxycorti- sol/corticosterone secretion increases in MeSO2-DDE-exposed cultured human adrenal slices. The adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane (o,p´- DDD, Mitotane®) is also bound in ZF/ZR but does not to impair hormone secretion in human adrenal slices at equimolar concentration. A targeted, presumably CYP1B1-catalysed irreversible binding of the adrenocorticolytic carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in ZF/ZR occurs in rat adrenal slices, whereas presumably CYP1A1-catalysed irreversible binding in endothelial cells is observed in CYP1-induced rats and mice. The rat-specific adrenocorticolytic activity of DMBA may rely on two independent pathological processes resulting in cell death and haemorrhage in the adrenal cortex. In Atlantic cod, selective binding of o,p´-DDD is observed in interrenal cells in cultured anterior kidney slices. In conclusion, precision-cut adrenal slice culture is a simple ex vivo test system with which to investigate CYP-catalysed metabolite binding, alteredsteroid hormone secretion and target cell ultrastructure in human, experimental and ...