Sulphide quinone reductase contributes to hydrogen sulphide metabolism in murine peripheral tissues but not in the CNS
Sulphide quinone reductase contributes to hydrogen sulphide metabolism in murine peripheral tissues but not in the CNS
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DOI：
10.1111/j.1476-5381.2011.01681.x
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发表时间：
2012-04-01
影响因子：
7.3
通讯作者：
Szurszewski, J. H.
中科院分区：
文献类型：
--
作者：
Linden, D. R.;Furne, J.;Szurszewski, J. H.
背景与目的
硫化氢（H₂S）作为一种气体信号分子正逐渐被接受。然而，有关信号终止的机制尚不清楚。我们使用了硫化物醌还原酶（SQR）的抑制剂——斯替加特林和抗霉素A，来验证H₂S的分解代谢涉及SQR这一假设。
实验方法
采用气相色谱法和高效液相色谱法测定活的且完整的小鼠大脑、肝脏和结肠肌层中H₂S的产生和消耗。通过逆转录聚合酶链反应（RT - PCR）和免疫组织化学方法测定SQR、乙基丙二酸脑病1（Ethe1）和硫代硫酸盐转移酶（TST；硫氰酸酶）的表达。
关键结果
在结肠肌层中，H₂³⁵S被分解代谢为[³⁵S]-硫代硫酸盐和[³⁵S]-硫酸盐，斯替加特林既降低了H₂³⁵S的消耗，也减少了[³⁵S]-硫代硫酸盐的形成。斯替加特林还增强了结肠肌层释放H₂S的能力。在大脑中，H₂³⁵S分解代谢为[³⁵S]-硫代硫酸盐和[³⁵S]-硫酸盐（此过程对斯替加特林不敏感），这部分解释了H₂³⁵S的消耗，而其余部分则以可能与蛋白质结合的未确定的³⁵S形式被捕获。编码SQR的mRNA水平在结肠肌层和肝脏中高于大脑。
结论与启示
这些数据支持这样一种概念，即结肠肌层内源性H₂S信号的终止部分是通过分解代谢为硫代硫酸盐和硫酸盐，且部分是通过一种涉及SQR的机制发生的。在大脑中，似乎H₂S信号的终止部分是通过蛋白质螯合，部分是通过不涉及SQR的分解代谢发生的。由于H₂S在人类疾病的动物模型中具有有益作用，我们认为选择性抑制SQR是药物研发的一个有吸引力的靶点。
BACKGROUND AND PURPOSEHydrogen sulphide (H2S) is gaining acceptance as a gaseous signal molecule. However, mechanisms regarding signal termination are not understood. We used stigmatellin and antimycin A, inhibitors of sulphide quinone reductase (SQR), to test the hypothesis that the catabolism of H2S involves SQR.EXPERIMENTAL APPROACHH2S production and consumption were determined in living and intact mouse brain, liver and colonic muscularis externa using gas chromatography and HPLC. Expressions of SQR, ethylmalonic encephalopathy 1 (Ethe1) and thiosulphate transferase (TST; rhodanese) were determined by RT-PCR and immunohistochemistry.KEY RESULTSIn the colonic muscularis externa, H2 35S was catabolized to [35S]-thiosulphate and [35S]-sulphate, and stigmatellin reduced both the consumption of H2 35S and formation of [35S]-thiosulphate. Stigmatellin also enhanced H2S release by the colonic muscularis externa. In the brain, catabolism of H2 35S to [35S]-thiosulphate and [35S]-sulphate, which was stigmatellin-insensitive, partially accounted for H2 35S consumption, while the remainder was captured as unidentified 35S that was probably bound to proteins. Levels of mRNA encoding SQR were higher in the colonic muscularis externa and the liver than in the brain.CONCLUSIONS AND IMPLICATIONSThese data support the concept that termination of endogenous H2S signalling in the colonic muscularis externa occurs via catabolism to thiosulphate and sulphate partially via a mechanism involving SQR. In the brain, it appears that H2S signal termination occurs partially through protein sequestration and partially through catabolism not involving SQR. As H2S has beneficial effects in animal models of human disease, we suggest that selective inhibition of SQR is an attractive target for pharmaceutical development.