Metabolic activation and toxicity of a DDT-metabolite, 3-methylsulphonyl-DDE, in the adrenal zona fasciculata in mice.
Whole-body autoradiography of 14C-labelled 3-methylsulphonyl-DDE (3-MeSO2-DDE) in female C57BL mice revealed a heavy accumulation in the adrenal cortex. Fairly high radioactivity appeared in the nasal mucosa and fat, while the labelling of the liver was intermediate. The adrenal radioactivity remained largely unextracted in tissue-sections treated with organic solvents. In the liver and intestinal contents the radioactivity was partly extracted, whereas in all other tissues almost completely extracted. According to light microscopic autoradiography, the tissue-bound adrenal radioactivity was confined to the zona fasciculata, leaving the other adrenal zones devoid of bound material. Incubation of 3-MeSO2-DDE with adrenal tissue (300 X g supernatant) revealed a dose- and time-dependent covalent binding to protein and formation of water-soluble metabolites. The cytochrome P-450 inhibitors metyrapone and carbon monoxide inhibited both covalent binding and polar metabolite formation. Addition of reduced glutathione decreased binding, while polar metabolite formation was increased. Histopathological examination of adrenals from 3-MeSO2-DDE-treated mice revealed extensive vacuolation and necrosis of the zona fasciculata 1-12 days after single doses down to 25 mg/kg. Degenerative changes were observed at 12.5 mg/kg. In contrast to 3-MeSO2-DDE, 14C-labelled 3,3'-bis(methylsulphonyl)-DDE was not accumulated in the adrenal cortex. 3-MeSO2-DDE is thus a persistent environmental pollutant with a unique ability to produce acute toxicity subsequent to metabolic activation in a mammalian tissue.
Lund
B O
BO
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala Biomedical Center.
Bergman
A
A
Brandt
I
I
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D011485:Protein Binding / Q000187:drug effects; D014018:Tissue Distribution
D065607:Cytochrome P-450 Enzyme Inhibitors; D004852:Epoxy Compounds; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; C013690:styrene oxide; D004851:Epoxide Hydrolases; D005978:Glutathione; D008797:Metyrapone