© 1991 Oxford University Press
research-article |
Adrenocortical Toxicity of 3-Methylsulfonyl-DDE in Mice
II. Mitochondrial Changes following Ecologically Relevant Doses
*Department of Pharmacology and Toxicology, Faculty of Veterinari Medicine, Swedish University of Agricultural Sciences Biomedicum, Box 573, S- 751 23 Uppsala
Department of Anatomy and Histology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences Box 7011, S-750 07 Uppsala
Environmental Chemistry, Wallenberg Laboratory, Stockholm University S-106 91 Stockholm, Sweden
Received January 9, 1990; accepted October 19, 1990
Transmission electron microscopy was used to characterize early ultrastructural lesions in the adrenal zona fasciculata of female C57BL mice given a single ip injection of the adrenocorticolytic DDT-metabolite 3- methylsulfonyl-DDE (MCSO2-DDE Following 3 mg/kg, mitochondrial changes were observed 6 hr after dosing. At 12 and 24 hr the mitochondrial changes were conspicuous, with disorganization and disappearance of central cristae. At doses of 6, 12, and 25 mg/kg body wt initial (6 hr) mitochondrial vacuolization was observed, followed by disappearance of mitochondria (6–12 mg/kg) or cellular necrosis (25 mg/kg). The metabolic activation and binding of MeSO2-[14C]DDE in adrenal homogenates were determined in vitro. The irreversible binding of MeSO2-[14C] to the mitochondria-containing adrenal S-9 pellet fraction was 50 times higher than that to the postmitochondrial S-12 supernatant fraction. The apparent Km was 2.1 µM and the apparent Vmax was 104 pmol/mg protein/30 mm for the binding of MeSO2-[14C] to S-0.3 supernatants. The irreversible protein binding was inhibited by metyrapone (K1=1 µM) and 11-deoxycorticosterone (K1=3 µM). In conclusion, the adrenal metabolic activation of MeSO2-[14C]DDE is suggested to be mediated by a mitochondrial cytochrome P450 form, presumably P450 (11ß). A primary mitochondrial lesion develops and subsequently leads to degeneration and necrosis of the zona fasciculata.