Adrenocortical toxicity of 3-methylsulfonyl-DDE in mice. II. Mitochondrial changes following ecologically relevant doses.
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 (MeSO2-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]DDE 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 microM and the apparent Vmax was 104 pmol/mg protein/30 min for the binding of MeSO2-[14C]DDE to S-0.3 supernatants. The irreversible protein binding was inhibited by metyrapone (Ki = 1 microM) and 11-deoxycorticosterone (Ki = 3 microM). In conclusion, the adrenal metabolic activation of MeSO2-DDE is suggested to be mediated by a mitochondrial cytochrome P450 form, presumably P450 (11 beta). A primary mitochondrial lesion develops and subsequently leads to degeneration and necrosis of the zona fasciculata.
Jönsson
C J
CJ
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala.
Rodriguez-Martinez
H
H
Lund
B O
BO
Bergman
A
A
Brandt
I
I
D000302:Adrenal Cortex / Q000187:drug effects*; D000818:Animals; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects*; D011485:Protein Binding
D004785:Environmental Pollutants; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene