Inhibition of leucine enkephalin metabolism in rat blood, plasma and tissues in vitro by an aminoboronic acid derivative.
Boroleucine, an aminoboronic acid derivative, is a potent inhibitor of aminopeptidases. Its effects on leucine enkephalin metabolism in rat whole blood, plasma and skeletal muscle and brain homogenates were determined in vitro. In the absence of the inhibitor, leucine enkephalin disappeared very rapidly from each medium. The rank order of metabolism rates was brain greater than muscle greater than whole blood approximately plasma. Des-tyrosyl-leucine enkephalin rapidly appeared as a result of metabolism by aminopeptidases. In whole blood and in the muscle and brain homogenates the aminopeptidase metabolite could account for all of the lost leucine enkephalin. In plasma, however, it appeared that another metabolic route contributed. Boroleucine prolonged the leucine enkephalin degradation half-life 1.6-1.9-fold in each medium at 0.1 microM concentrations, 1/1000th the concentration of leucine enkephalin. At 1.0 microM boroleucine concentrations the half-lives were prolonged 4.0-6.4-fold. Boroleucine also inhibited the degradation of des-tyrosyl-leucine enkephalin added to whole blood, but did not inhibit its degradation in muscle or brain homogenates. Boroleucine and other aminoboronic acid derivatives may be useful tools for studying peptide metabolism, and as pharmaceutical adjuvants to inhibit the degradation of peptide drugs metabolized by aminopeptidases.
Hussain
M A
MA
Medical Products Department, DuPont Company, Wilmington, DE 19880-0400.
Rowe
S M
SM
Shenvi
A B
AB
Aungst
B J
BJ
D000818:Animals; D001896:Boron Compounds; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D006207:Half-Life; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D001896:Boron Compounds; C064506:boroleucine; D004743:Enkephalin, Leucine; D007930:Leucine