Duncan G S, Wolberg G, Schmitges C J, Deeprose R D, Zimmerman T P
J Immunopharmacol. 1982;4(1-2):79-100. doi: 10.3109/08923978209031077.
The adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), at low concentrations (less than 10 microM), enhances the inhibitory activity of adenosine against lymphocyte-mediated cytolysis (LMC) without itself being inhibitory. At higher concentrations, EHNA alone is inhibitory to LMC with an IC50 of 160 microM. This inhibition is reversible upon washout, appears to affect an early stage of the lytic process, and does not appear to involve changes in basal levels of cyclic AMP (cAMP), ribonucleoside 5'-triphosphate pool sizes, S-adenosylhomocysteine levels, or protein carboxymethylation. EHNA does enhance the cAMP response of cytolytic lymphocytes (CL) to activators of adenylate cyclase such as prostaglandin E1. EHNA inhibits lymphocyte high-affinity cAMP phosphodiesterase at immunosuppressive levels, exhibiting hyperbolic mixed-type inhibition (Ki = 83 microM, alpha = 0.47, beta = 0.18). Whereas inhibition of intralymphocytic ADA is complete at low concentrations (less than 25 microM) of EHNA, inhibition of LMC and intralymphocytic cAMP phosphodiesterase increases linearly with EHNA concentration to at least 200 microM. The presence of 200 microM EHNA during the centrifugation of mixtures of CL and EL4 leukemia target cells leads to increased CL cAMP levels. 2'-Deoxycoformycin, a more potent ADA inhibitor than EHNA, is not inhibitory to LMC and shows none of these cAMP-related effects. These results suggest that CL-target cell contact stimulates adenylate cyclase in the CL and that EHNA inhibits LMC due to its enhancement of this target cell-stimulated elevation of cAMP.
腺苷脱氨酶（ADA）抑制剂赤藓红 -9-（2-羟基 -3-壬基）腺嘌呤（EHNA）在低浓度（低于10微摩尔）时，可增强腺苷对淋巴细胞介导的细胞溶解（LMC）的抑制活性，而其本身并无抑制作用。在较高浓度时，单独的EHNA对LMC具有抑制作用，IC50为160微摩尔。这种抑制作用在洗脱后是可逆的，似乎影响溶解过程的早期阶段，并且似乎不涉及环磷酸腺苷（cAMP）基础水平、核糖核苷5'-三磷酸池大小、S-腺苷同型半胱氨酸水平或蛋白质羧甲基化的变化。EHNA确实增强了溶细胞性淋巴细胞（CL）对腺苷酸环化酶激活剂（如前列腺素E1）的cAMP反应。EHNA在免疫抑制水平下抑制淋巴细胞高亲和力cAMP磷酸二酯酶，表现为双曲线混合型抑制（Ki = 83微摩尔，α = 0.47，β = 0.18）。虽然在低浓度（低于25微摩尔）的EHNA下，淋巴细胞内ADA的抑制作用是完全的，但对LMC和淋巴细胞内cAMP磷酸二酯酶的抑制作用随EHNA浓度线性增加至至少200微摩尔。在CL和EL4白血病靶细胞混合物离心过程中存在200微摩尔EHNA会导致CL的cAMP水平升高。2'-脱氧助间型霉素是一种比EHNA更有效的ADA抑制剂，对LMC无抑制作用，也没有这些与cAMP相关的效应。这些结果表明，CL与靶细胞的接触刺激了CL中的腺苷酸环化酶，并且EHNA抑制LMC是由于其增强了这种靶细胞刺激引起的cAMP升高。
