Thimet oligopeptidase EC 3.4.24.15 is a major liver kininase

Bradykinin (BK) is a potent hepato-portal hypertensive agent although it is efficiently inactivated by the liver. The organ converts angiotensin I to All, but at a much slower rate than it inactivates BK, We had previously id entified EC 3.4.24.15 as an hepatic bradykinin inactivating endopeptidase t hat hydrolyzes BE; at the F-5-S-6 bond. The aim of this study was to determ ine the relative importance of BIE, as compared to other kininases, in norm al, cirrhotic or inflamed rat livers, as well as in samples of human liver. Using specific substrates and inhibitors we showed that: 1) purified BIE p reparation hydrolyzed BE( and a BK analogue (BK-Q) with similar efficacy; B K-Q was functionally active since it caused an increase in hepato-portal pr essure, as did BK itself. 2) BK degradation in rat serum was performed by A CE since BIE and prolylendopeptidase (PEP) activities were negligible. 3) n ormal rat liver homogenate contained a large amount of BIE activity which w as eliminated by a specific EC 3.4.24.15 inhibitor; ACE and PEP activities were negligible. 4) Then was no difference (p>0.05) in BIE activity in the liver homogenates from rats with normal, inflamed or cirrhotic livers. 5) B IE activity was efficiently removed from livers (normal, inflamed or cirrho tic) that were perfused with TritonX-100. 6) Human liver had an similar enz ymatic pattern although ACE activity was detected. We concluded that in nor mal, inflamed or cirrhotic rat livers, as well as in the human liver, the b radykinin inactivating endopeptidase CEC 3.3.24.15), and not ACE, is the ma jor hepatic kininase. (C) 2000 Elsevier Science inc. All rights reserved.