The Cysteine Dioxgenase Knockout Mouse: Altered Cysteine Metabolism in Nonhepatic Tissues Leads to Excess H2S/HS- Production and Evidence of Pancreatic and Lung Toxicity
The Cysteine Dioxgenase Knockout Mouse: Altered Cysteine Metabolism in Nonhepatic Tissues Leads to Excess H2S/HS- Production and Evidence of Pancreatic and Lung Toxicity
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DOI：
10.1089/ars.2012.5010
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发表时间：
2013-10-20
影响因子：
6.6
通讯作者：
Stipanuk, Martha H.
中科院分区：
文献类型：
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作者：
Roman, Heather B.;Hirschberger, Lawrence L.;Stipanuk, Martha H.
目的：为了确定半胱氨酸双加氧酶（CDO）损失对组织水平半胱氨酸代谢的影响，我们测定了相关代谢物和酶的水平以及喂食无牛磺酸或补充牛磺酸饮食的CDO-/-小鼠肝脏、胰腺、肾脏和肺中H2S/HS-（气态硫化氢及其共轭碱）毒性的证据。结果：CDO-/-小鼠具有低组织和血清牛磺酸和亚牛磺酸水平以及高组织半胱氨酸水平，与CDO的丧失一致。CDO-/-小鼠尿中硫代硫酸盐排泄量升高，组织和血清中胱硫醚和羊毛硫醚水平升高，细胞色素c氧化酶抑制和不稳定的证据，这与H2S/HS-的过量产生一致。胱硫醚和羊毛硫醚的积累似乎是由于胱硫醚合酶（CBS）介导的半胱氨酸脱水。观察到野生型小鼠的胰腺中非常高水平的亚牛磺酸和CDO-/-小鼠的胰腺中非常高水平的胱硫醚和羊毛硫醚，表明胰腺中独特的半胱氨酸代谢。创新：CDO-/-小鼠模型为组织特异性半胱氨酸代谢提供了新的见解，特别是胰腺在通过CBS催化反应代谢过量半胱氨酸中的作用，并且将是研究过量内源性产生H2S/HS-的影响的有用模型。结论：CDO-/-小鼠清楚地表明，组织中的H2S/HS-产生可超过动物将硫化物氧化成硫酸盐的能力，并表明胰腺和肺比肝脏和肾脏更容易受到内源性H2S/HS（-）产生的毒性的影响。抗氧化剂。氧化还原信号。19，1321-1336.
Aims: To define the consequences of loss of cysteine dioxygenase (CDO) on cysteine metabolism at the tissue level, we determined levels of relevant metabolites and enzymes and evidence of H2S/HS- (gaseous hydrogen sulfide and its conjugate base) toxicity in liver, pancreas, kidney, and lung of CDO-/- mice that were fed either a taurine-free or taurine-supplemented diet. Results: CDO-/- mice had low tissue and serum taurine and hypotaurine levels and high tissue levels of cysteine, consistent with the loss of CDO. CDO-/- mice had elevated urinary excretion of thiosulfate, high tissue and serum cystathionine and lanthionine levels, and evidence of inhibition and destabilization of cytochrome c oxidase, which is consistent with excess production of H2S/HS-. Accumulation of cystathionine and lanthionine appeared to result from cystathionine -synthase (CBS)-mediated cysteine desulfhydration. Very high levels of hypotaurine in pancreas of wild-type mice and very high levels of cystathionine and lanthionine in pancreas of CDO-/- mice were observed, suggesting a unique cysteine metabolism in the pancreas. Innovation: The CDO-/- mouse model provides new insights into tissue-specific cysteine metabolism, particularly the role of pancreas in metabolism of excess cysteine by CBS-catalyzed reactions, and will be a useful model for studying the effects of excess endogenous production of H2S/HS-. Conclusion: The CDO-/- mouse clearly demonstrates that H2S/HS- production in tissues can exceed the capacity of the animal to oxidize sulfide to sulfate and demonstrates that pancreas and lung are more susceptible to toxicity from endogenous H2S/HS(-)production than are liver and kidney. Antioxid. Redox Signal. 19, 1321-1336.