title: Thimet oligopeptidase EC 3.4.24.15 is a major liver kininase.
abstract: Bradykinin (BK) is a potent hepato-portal hypertensive agent although it is efficiently inactivated by the liver. The organ converts angiotensin I to AII, but at a much slower rate than it inactivates BK. We had previously identified EC 3.4.24.15 as an hepatic bradykinin inactivating endopeptidase that hydrolyzes BK at the F5-F6 bond. The aim of this study was to determine the relative importance of BIE, as compared to other kininases, in normal, cirrhotic or inflamed rat livers, as well as in samples of human liver. Using specific substrates and inhibitors we showed that: 1) purified BIE preparation hydrolyzed BK and a BK analogue (BK-Q) with similar efficacy; BK-Q was functionally active since it caused an increase in hepato-portal pressure, as did BK itself. 2) BK degradation in rat serum was performed by ACE since BIE and prolylendopeptidase (PEP) activities were negligible. 3) normal rat liver homogenate contained a large amount of BIE activity which was eliminated by a specific EC 3.4.24.15 inhibitor; ACE and PEP activities were negligible. 4) There was no difference (p>0.05) in BIE activity in the liver homogenates from rats with normal, inflamed or cirrhotic livers. 5) BIE activity was efficiently removed from livers (normal, inflamed or cirrhotic) that were perfused with TritonX-100.6) Human liver had an similar enzymatic pattern although ACE activity was detected. We concluded that in normal, inflamed or cirrhotic rat livers, as well as in the human liver, the bradykinin inactivating endopeptidase (EC 3.4.24.15), and not ACE, is the major hepatic kininase.
authors.affiliation: Department of Biochemistry, Universidade Federal de São Paulo, Brazil.
authors.forename: H M
authors.initials: HM
authors.lastname: Molina
authors.forename: A K
authors.initials: AK
authors.lastname: Carmona
authors.forename: M
authors.initials: M
authors.lastname: Kouyoumdjian
authors.forename: D R
authors.initials: DR
authors.lastname: Borges
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000511:alpha-Macroglobulins; D010450:Endopeptidases; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; C032615:bradykinin kininase; D001920:Bradykinin