Bäck M, Kumlin M, Cotgreave I A, Dahlén S E
Experimental Asthma & Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Br J Pharmacol. 2001 Aug;133(7):1134-44. doi: 10.1038/sj.bjp.0704180.
Contractions of guinea-pig tracheal preparations to cysteinyl-leukotrienes (LTC(4), LTD(4) and LTE(4)) were characterized in organ baths, and cysteinyl-leukotriene metabolism was studied using radiolabelled agonists and RP-HPLC separation. In the presence of S-hexyl GSH (100 microM) the metabolism of [(3)H]-LTC(4) into [(3)H]-LTD(4) was inhibited and the LTC(4)-induced contractions were resistant to CysLT(1) receptor antagonism but inhibited by the dual CysLT(1)/CysLT(2) receptor antagonist BAY u9773 (0.3 - 3 microM) with a pA(2)-value of 6.8+/-0.2. In the presence of L-cysteine (5 mM), the metabolism of [(3)H]-LTD(4) into [(3)H]-LTE(4) was inhibited and the LTD(4)-induced contractions were inhibited by the CysLT(1) receptor antagonist ICI 198,615 (1 - 10 nM) with a pA(2)-value of 9.3+/-0.2. However, at higher concentrations of ICI 198,615 (30 - 300 nM) a residual contraction to LTD(4) was unmasked, and this response was inhibited by BAY u9773 (1 - 3 microM). In the presence of the combination of S-hexyl GSH with L-cysteine, the LTD(4)-induced contractions displayed the characteristics of the LTC(4) contractile responses, i.e. resistant to CysLT(1) receptor antagonism, increased maximal contractions and slower time-course. This qualitative change of the LTD(4)-induced contraction was also observed in the presence of S-decyl GSH (100 microM), GSH (10 mM) and GSSG (10 mM). S-hexyl GSH, S-decyl GSH, GSH and GSSG all stimulated a formation of [(3)H]-LTC(4) from [(3)H]-LTD(4). In conclusion, GSH and GSH-related compounds changed the pharmacology of the LTD(4)-induced contractions by stimulating the conversion of LTD(4) into LTC(4). Moreover, the results indicate that, in addition to the metabolism of LTC(4) into LTD(4) and LTE(4), also the formation of LTC(4) from LTD(4) may regulate cysteinyl-leukotriene function.
在器官浴槽中研究了豚鼠气管制剂对半胱氨酰白三烯（LTC₄、LTD₄和LTE₄）的收缩反应，并使用放射性标记的激动剂和反相高效液相色谱分离法研究了半胱氨酰白三烯的代谢。在存在S-己基谷胱甘肽（100 μM）的情况下，[(³H]-LTC₄向[(³H]-LTD₄的代谢受到抑制，LTC₄诱导的收缩对CysLT₁受体拮抗作用具有抗性，但被双重CysLT₁/CysLT₂受体拮抗剂BAY u9773（0.3 - 3 μM）抑制，pA₂值为6.8±0.2。在存在L-半胱氨酸（5 mM）的情况下，[(³H]-LTD₄向[(³H]-LTE₄）的代谢受到抑制，LTD₄诱导的收缩被CysLT₁受体拮抗剂ICI 198,615（1 - 10 nM）抑制，pA₂值为9.3±0.2。然而，在较高浓度的ICI 198,615（30 - 300 nM）时，对LTD₄的残余收缩被揭示出来，并且这种反应被BAY u9773（1 - 3 μM）抑制。在存在S-己基谷胱甘肽与L-半胱氨酸的组合时，LTD₄诱导的收缩表现出LTC₄收缩反应的特征，即对CysLT₁受体拮抗作用具有抗性、最大收缩增加和时程减慢。在存在S-癸基谷胱甘肽（100 μM）、谷胱甘肽（10 mM）和氧化型谷胱甘肽（10 mM）的情况下也观察到了LTD₄诱导收缩的这种定性变化。S-己基谷胱甘肽、S-癸基谷胱甘肽、谷胱甘肽和氧化型谷胱甘肽均刺激了[(³H]-LTC₄从[(³H]-LTD₄的形成。总之，谷胱甘肽和与谷胱甘肽相关的化合物通过刺激LTD₄向LTC₄的转化改变了LTD₄诱导收缩的药理学特性。此外，结果表明，除了LTC₄向LTD₄和LTE₄的代谢外，LTD₄向LTC₄的形成也可能调节半胱氨酰白三烯的功能。
