Atanasov Atanas G, Tam Steven, Röcken Jens M, Baker Michael E, Odermatt Alex
Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Berne CH-3010, Switzerland.
Biochem Biophys Res Commun. 2003 Aug 22;308(2):257-62. doi: 10.1016/s0006-291x(03)01359-7.
Dithiocarbamates (DTCs), important therapeutic and industrial chemicals released in high quantities into the environment, exhibit complex chemical and biological activities. Here, we demonstrate an effect of DTCs on glucocorticoid action due to inhibition of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 2, converting cortisol to cortisone in the kidney, but not 11 beta-HSD1, catalyzing the reverse reaction in liver and adipose tissue. Thus, DTCs may locally increase active glucocorticoid concentrations. Preincubation with the DTC thiram abolished 11 beta-HSD2 activity, suggesting irreversible enzyme inhibition. The sulfhydryl protecting reagent dithiothreitol blocked thiram-induced inhibition and NAD+ partially protected 11 beta-HSD2 activity, indicating that DTCs act at the cofactor-binding site. A 3D-model of 11 beta-HSD2 identified Cys90 in the NAD(+)-binding site as a likely target of DTCs, which was supported by a 99% reduced activity of mutant Cys90 to serine. The interference of DTCs with glucocorticoid-mediated responses suggests a cautious approach in the use of DTCs in therapeutic applications and in exposure to sources of DTCs such as cosmetics and agricultural products by pregnant women and others.
二硫代氨基甲酸盐（DTCs）是大量释放到环境中的重要治疗性和工业化学品，具有复杂的化学和生物活性。在此，我们证明了DTCs对糖皮质激素作用的影响，这是由于其抑制了2型11β-羟基类固醇脱氢酶（11β-HSD），该酶在肾脏中将皮质醇转化为可的松，但不抑制11β-HSD1，后者在肝脏和脂肪组织中催化相反的反应。因此，DTCs可能会局部增加活性糖皮质激素的浓度。用DTC福美双预孵育可消除11β-HSD2的活性，表明酶被不可逆抑制。巯基保护试剂二硫苏糖醇可阻断福美双诱导的抑制作用，而NAD+可部分保护11β-HSD2的活性，这表明DTCs作用于辅因子结合位点。11β-HSD2的三维模型确定NAD(+)结合位点中的Cys90可能是DTCs的作用靶点，这一点得到了Cys90突变为丝氨酸后活性降低99%的支持。DTCs对糖皮质激素介导反应的干扰表明，在治疗应用中使用DTCs以及孕妇和其他人接触DTCs来源（如化妆品和农产品）时应谨慎行事。
