The effects of anti-TNF-alpha antibody and dexamethasone on TCDD-induced oxidative stress in mice.
Recent studies have implicated tumor necrosis factor alpha (TNF-alpha) in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since TNF-alpha sensitizes and activates phagocytic cells to agents that induce them to release reactive oxygen species, TNF-alpha may act as an amplifying loop in TCDD-induced oxidative stress (OS). Therefore, the effects of anti-TNF-alpha antibody (40 micrograms/mouse) and dexamethasone (2 mg/kg) treatment on TCDD-induced OS as measured by DNA single-strand breaks (SSB) in hepatic nuclei, lipid peroxidation in hepatic mitochondria and microsomes, and activation of peritoneal lavage cells (PLC) in C57BL/6J mice were studied. One day after treatment with 125 micrograms TCDD/kg, anti-TNF-alpha resulted in 70, 27, 33 and 21% decreases in DNA-SSB, mitochondrial and microsomal lipid peroxidation and PLC activation, respectively, relative to TCDD-treated mice. Dexamethasone produced 8, 32, 35 and 9% decreases in DNA-SSB, mitochondrial and microsomal lipid peroxidation and PLC activation, respectively, in TCDD-treated animals. The combination of anti-TNF-alpha and dexamethasone resulted in 67, 55, 61 and 25% decreases in the above parameters of OS, respectively. The results suggest that TNF-alpha release may play a role in sensitizing and activating phagocytic cells following treatment with TCDD, contributing to the overall OS of animals following exposure to TCDD.
Alsharif
N Z
NZ
Department of Pharmaceutical Sciences, Creighton University Health Sciences Center, Omaha, Nebr.
Hassoun
E
E
Bagchi
M
M
Lawson
T
T
Stohs
S J
SJ
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D004249:DNA Damage; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010537:Peritoneum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
D000888:Antibodies, Anti-Idiotypic; D000072317:Polychlorinated Dibenzodioxins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone