Effects of acute gamma-hexachlorocyclohexane intoxication in relation to the redox regulation of nuclear factor-kappa B cytokine gene expression, and liver injury in the rat

Videla LA.; Tapia, G; Varela, P; Cornejo P.; Guerrero, J; Israel, Y; Fernández V.

Abstract

?-Hexachlorocyclohexane-induced hepatotoxicity is associated with oxidative stress. We tested the hypothesis that ?-hexachlorocyclohexane triggers the redox activation of nuclear factor-?B (NF-?B), leading to proinflammatory cytokine expression. Liver NF-?B activation (electrophoretic mobility shift assay), tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) mRNA expression (reverse transcription-polymerase chain reaction), and their serum levels (enzyme-linked immunosorbent assay) were measured at different times after ? -hexachlorocyclohexane treatment (50 mg/kg). The relationship between these and hepatic O2 uptake, glutathione and protein carbonyl levels, and sinusoidal lactate dehydrogenase (LDH) efflux in liver perfusion studies was determined. ?-Hexachlorocyclohexane increased liver NF-?B DNA binding at 14-22 h after treatment, concomitantly with significant glutathione depletion and an increase in the rate of O2 consumption, the content of protein carbonyls, and the sinusoidal LDH efflux. In these conditions, the expression of TNF-? and IL-1? is enhanced, with maximal increases in their respective mRNA content and serum levels of the cytokines being elicited at 18 h after ?-hexachlorocyclohexane treatment. All these changes are suppressed by the administration of ?-tocopherol (100 mg/kg) or the Kupffer cell inactivator gadolinium chloride (10 mg/kg) prior to ?-hexachlorocyclohexane. ?-Hexachlorocyclohexane-induced TNF-? levels in serum are suppressed by pretreatment with an antisense oligonucleotide (ASO TJU-2755; daily doses of 10 mg/kg for 2 days) targeting the primary transcript for the cytokine, whereas those of IL-1? are not modified. It is concluded that ?-hexachlorocyclohexane-induced liver oxidative stress triggers the DNA binding activity of NF-?B, with the consequent increase in the expression of NF-?B-dependent genes for TNF-? and for IL-1?, factors that may mediate the hepatotoxicity of the insecticide.

Más información

Título según WOS: Effects of acute gamma-hexachlorocyclohexane intoxication in relation to the redox regulation of nuclear factor-kappa B cytokine gene expression, and liver injury in the rat
Título según SCOPUS: Effects of Acute ?-Hexachlorocyclohexane Intoxication in Relation to the Redox Regulation of Nuclear Factor-?B, Cytokine Gene Expression, and Liver Injury in the Rat
Título de la Revista: ANTIOXIDANTS & REDOX SIGNALING
Volumen: 6
Número: 2
Editorial: Mary Ann Liebert Inc.
Fecha de publicación: 2004
Página de inicio: 471
Página final: 480
Idioma: English
URL: http://www.liebertonline.com/doi/abs/10.1089/152308604322899530
DOI:

10.1089/152308604322899530

Notas: ISI, SCOPUS