Benznidazole-induced ultrastructural alterations in rat adrenal cortex. Mechanistic studies.
Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole acetamide) is a drug used against Chagas' disease, a parasitic disease afflicting several millions of Latin Americans. Bz administration to Sprague-Dawley male rats at 100 mg/kg p.o. caused subcellular alterations in the adrenal cortex involving fasciculata and reticularis zones but not in the glomerulosa. There is Bz nitroreductase activity in the adrenal microsomal and mitochondrial fractions but most of it is localized in mitochondria. Activity in the two fractions requires NADPH under anaerobic conditions. Mitochondrial Bz nitroreductase activity was inhibited by oxygen. A minor but statistically significant inhibition was observed in mixtures incubated under carbon monoxide. Microsomal Bz nitroreductase activity was not detected under oxygen atmosphere and was not inhibited under carbon monoxide. No Bz nitroreductase activity mediated by xanthine oxidase or aldehyde oxidase was detected in the cytosolic fraction from rat adrenals. Electron microscopic examination of the adrenal cortex from Bz-treated animals revealed cells with marked lipid accumulation and alterations in nuclei, endoplasmic reticulum and mitochondria in the reticularis and fasciculata zones. In vitro results suggest a Bz nitroreductive activation, with minor or null P-450 participation, leading to reactive metabolites able to cause damage in various organelles.
de Castro
C R
CR
Centro de Investigaciones Toxicológicas (CEITOX) CITEFA/CONICET, Prov. de Buenos Aires, Argentina.
Diaz de Toranzo
E G
EG
Castro
J A
JA
D000284:Administration, Oral; D000302:Adrenal Cortex / Q000187:drug effects* / Q000648:ultrastructure; D000818:Animals; D008297:Male; D008854:Microscopy, Electron; D008861:Microsomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D009153:Mutagens / Q000633:toxicity; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000633:toxicity*; D009601:Nitroreductases / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000201:enzymology
D009153:Mutagens; D009593:Nitroimidazoles; C029492:aromatic NADH-dependent nitroreductase; D009601:Nitroreductases; C009999:benzonidazole