Septic shock is mediated in part by nitric oxide (NO) and tumour necrosis factor α (TNFα). NO is synthesized primarily from extracellular arginine. We tested the ability of an arginine-degrading enzyme to inhibit NO production in mice and to protect mice from the hypotension and lethality that occur after the administration of TNFα or endotoxin. Treatment of BALB/c mice with arginine deiminase (ADI) formulated with succinimidyl succinimide polyethylene glycol of Mr 20000 (ADI-SS PEG20000) eliminated all measurable plasma arginine (from normal levels of ∼155μM arginine to 2μM). In addition, ADI-SS PEG20000 also inhibited the production of NO, as quantified by plasma nitrate+nitrite. Treatment of mice with TNFα or endotoxin resulted in a dose-dependent increase in NO production and lethality. Pretreatment of mice with ADI-SS PEG20000 resulted in increased resistance to the lethal effects of TNFα and endotoxin. These observations are consistent with NO production resulting, to some extent, from the metabolism of extracellular arginine. The toxic effects of TNFα and endotoxin may be partially inhibited by enzymic degradation of plasma arginine by ADI-SS PEG20000. Interestingly, pretreatment with ADI-SS PEG20000 did not inhibit the anti-tumour activity of TNFα in vitro or in vivo. This treatment may allow greater amounts of TNFα, as well as other cytokines, to be administered while abrogating side effects such as hypotension and death.
Enzymic degradation of plasma arginine using arginine deiminase inhibits nitric oxide production and protects mice from the lethal effects of tumour necrosis factor α and endotoxin
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J. Brandon THOMAS, Frederick W. HOLTSBERG, C. Mark ENSOR, John S. BOMALASKI, Mike A. CLARK; Enzymic degradation of plasma arginine using arginine deiminase inhibits nitric oxide production and protects mice from the lethal effects of tumour necrosis factor α and endotoxin. Biochem J 1 May 2002; 363 (3): 581–587. doi: https://doi.org/10.1042/bj3630581
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