Inhibition of human plasma leucine5-enkephalin aminopeptidase hydrolysis by various endogenous peptides and a select number of clinically used drugs.
We identified a number of clinically used drugs and biologically active endogenous peptides able to significantly decrease the rate of human plasmatic aminopeptidase (AP) leucine-enkephalin (LEU) degradation. Bacitracin, bestatin, fluvoxamine, and each of 4 peptides tested significantly increased, in a dose-dependent manner (10-10 M), LEU degradation half-life (t1/2) in each of 5 plasma samples studied. Each sample was obtained by pooling equal volume of 6 randomly selected, individual plasmas (4 male and 2 female healthy, drug-free volunteers). Thirty subjects (20 females and 10 males) participated in this study. With the exception of fluvoxamine, this inhibitory effect was lacking in various other commonly used drugs with widely different chemical structures and pharmacological profiles, eg, antidepressants (SSRIs, imipramine-like tricyclics, MAOIs), acute antimigraine agents (triptan class drugs), the nonselective beta-adrenergic antagonist propranolol, and serotonin receptor agonists and antagonists. Agents (concentration 10 M used as illustration), listed in decreasing order of LEU-AP inhibitory activity: substance P > angiotensin III > methionine-enkephalin > angiotensin II > fluvoxamine > bestatin gave t1/2 values (+/- SD) of 39.3 +/- 1.1, 29.4 +/- 0.8, 28.3 +/- 0.8, 27.4 +/- 0.7, 24.5 +/- 1.5, and 23.6 +/- 0.9 minutes, respectively. Control, bacitracin, and fluphenazine (known LEU-AP inhibitors were used for comparison) values of 11.8 +/- 1.0, 31.3 +/- 0.7, and 19.6 +/- 1.0 minutes, respectively. As expected, these drugs significantly decreased the initial velocity of peptide degradation; Iv values (+/- SD) of: 0.17 +/- 0.1 (0.02 +/- 0.01), 0.23 +/- 0.2 (0.02 +/- 0.01), 0.25 +/- 0.2 (0.02 +/- 0.01), 0.26 +/- 0.2 (0.03 +/- 0.01), 0.31 +/- 0.1 (0.03 +/- 0.01), and 0.33 +/- 0.1 (0.03 +/- 0.01), respectively; control, bacitracin, and fluphenazine: 1.10 +/- 0.3 (0.12 +/- 0.03), 0.20 +/- 0.1 (0.02 +/- 0.01), and 0.82 +/- 0.2 (0.08 +/- 0.02) pg LEU/min (pg LEU/mg protein/min), respectively. Results emphasize the selective nature of chemical structures required to significantly inhibit AP activity and provided information that could help the rational design of agents with high specificity in a biologic milieu containing multiple peptidases. In this case, targeted modulation of the bioavailability of LEU and other endogenous AP-degraded hormonal and nonhormonal peptides could be useful in the treatment of the pathophysiology associated with various disease conditions. Whether their development could find useful pharmacological applications remains to be explored.
Mosnaim
Aron D
AD
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, N. Chicago, Illinois 60064, USA. Aron.Mosnaim@rosalindfranklin.edu
Puente
Javier
J
Ranade
Vasant
V
Hoang
Catherine
C
Wolf
Marion E
ME
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004743:Enkephalin, Leucine / Q000097:blood / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D013287:Illicit Drugs / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D004364:Pharmaceutical Preparations / Q000737:chemistry; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D013287:Illicit Drugs; D010455:Peptides; D004364:Pharmaceutical Preparations; D017366:Serotonin Receptor Agonists; D004743:Enkephalin, Leucine; D000626:Aminopeptidases