Ashizawa N, Okumura H, Kobayashi F, Aotsuka T, Takahashi M, Asakura R, Arai K, Matsuura A
Pharmaceutical Research Laboratories, Sapporo Breweries Limited, Shizuoka, Japan.
Biol Pharm Bull. 1994 Feb;17(2):207-11. doi: 10.1248/bpb.17.207.
The effects of various metal chelators on endothelin (ET)-converting enzyme (ECE) activity were examined in vitro. Three chelators, 2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ), were found to dose-dependently inhibit ECE activity, but this inhibition was much weaker compared with EDTA. In the presence of Zn2+, the inhibitory activity of all these compounds, including EDTA, was abolished. The addition of Ca2+ and Mg2+ markedly attenuated the inhibitory activity of EDTA, but the other three chelators were still able to inhibit ECE. ECE, once inactivated by EDTA or 8-MQ, was reactivated by the addition of divalent cations such as Zn2+ and Mn2+. These compounds also inhibited angiotensin-converting enzyme activity in a manner similar to the inhibition exhibited towards ECE. Chelate-titration indicated that DMP, TDT and 8-MQ chelate Zn2+ but not Ca2+ and Mg2+. These results suggest that the ECE inhibition exhibited by these compounds is mainly attributable to their chelating activities. The metal-selective chelating activity by DMP, TDT and 8-MQ may contribute to the retention of ECE inhibition in the presence of Ca2+ and Mg2+.
在体外研究了各种金属螯合剂对内皮素（ET）转换酶（ECE）活性的影响。发现三种螯合剂，即2,3-二巯基-1-丙醇（DMP）、甲苯-3,4-二硫醇（TDT）和8-巯基喹啉（8-MQ）可剂量依赖性地抑制ECE活性，但与乙二胺四乙酸（EDTA）相比，这种抑制作用要弱得多。在存在锌离子（Zn2+）的情况下，包括EDTA在内的所有这些化合物的抑制活性均被消除。添加钙离子（Ca2+）和镁离子（Mg2+）可显著减弱EDTA的抑制活性，但其他三种螯合剂仍能抑制ECE。一旦ECE被EDTA或8-MQ灭活，通过添加二价阳离子如Zn2+和锰离子（Mn2+）可使其重新激活。这些化合物还以类似于对ECE的抑制方式抑制血管紧张素转换酶活性。螯合滴定表明，DMP、TDT和8-MQ螯合Zn2+，但不螯合Ca2+和Mg2+。这些结果表明，这些化合物对ECE的抑制作用主要归因于它们的螯合活性。DMP、TDT和8-MQ的金属选择性螯合活性可能有助于在存在Ca2+和Mg2+的情况下保持对ECE的抑制作用。
