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OtherANALGESIA AND DRUGS OF ABUSE

Almost Complete Protection from [Met5]-Enkephalin-Arg6-Gly7-Leu8(Met-enk-RGL) Hydrolysis in Membrane Preparations by the Combination of Amastatin, Captopril and Phosphoramidon

Toyokazu Hiranuma, Kayoko Iwao, Ken Kitamura, Teruhiko Matsumiya and Tetsuo Oka
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 769-774;
Toyokazu Hiranuma
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Kayoko Iwao
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Ken Kitamura
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Teruhiko Matsumiya
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Tetsuo Oka
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Abstract

The contents of [Met5]-enkephalin-Arg6-Gly7-Leu8(met-enk-RGL) and its seven hydrolysis products—Y, YG, YGG, YGGF, YGGFM, YGGFMR, and YGGFMRG—were estimated after incubating met-enk-RGL with a membrane fraction from either guinea pig ileum or striatum for various times at 37°C. After 15 min of incubation, met-enk-RGL was completely hydrolyzed in both the ileal and the striatal membrane preparations. The major hydrolysis products were YGGFMR, YGGF and Y, which indicates that dipeptidyl carboxypeptidase and aminopeptidase activities were mainly involved in the hydrolysis. Additionally, even when the ileal and the striatal preparations were incubated for 60 min in the presence of both captopril, a dipeptidyl carboxypeptidase inhibitor, and amastatin, an aminopeptidase inhibitor, 24% and 44% of enkephalin octapeptide, respectively, were hydrolyzed. The YGG fragment was the major hydrolysis product in both preparations. When the ileal and the striatal membrane fractions were incubated with met-enk-RGL in the presence of three peptidase inhibitors—captopril, amastatin, and phosphoramidon (an inhibitor of endopeptidase-24.11)—approximately 95% of the enkephalin octapeptide, remained intact in both cases. This shows that met-enk-RGL was almost exclusively hydrolyzed by three enzymes, amastatin-sensitive aminopeptidase, captopril-sensitive dipeptidyl carboxypeptidase I and phosphoramidon-sensitive endopeptidase-24.11, in both ileal and striatal membranes. We also reported the potencies of several opioids relative to that of met-enk-RGL in guinea pig ileum pretreated with the three peptidase inhibitors.

Footnotes

  • Send reprint requests to: Tetsuo Oka, Department of Pharmacology, School of Medicine, Tokai University, Isehara 259-11, Japan.

  • ↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

  • Abbreviations:
    met-enk
    [Met5]-enkephalin
    met-enk-RGL
    [Met5]-enkephalin-Arg6-Gly7-Leu8
    AsA
    amastatin-sensitive aminopeptidase(s)
    PsE
    phosphoramidon-sensitive endopeptidase-24.11 (“enkephalinase,” EC3.4.24.11)
    CsD
    captopril-sensitive dipeptidyl carboxypeptidase I (angiotensin 1 converting enzyme, kininase II, EC3.4.15.1)
    PI
    peptidase inhibitor
    CTOP
    d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2
    HPLC-ECD
    high-performance liquid chromatography combined with electrochemical detection. The standard one-letter, instead of three-letter, codes for amino acids were employed for the hydrolysis products of met-enk-RGL
    • Received November 5, 1996.
    • Accepted January 22, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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Almost Complete Protection from [Met5]-Enkephalin-Arg6-Gly7-Leu8(Met-enk-RGL) Hydrolysis in Membrane Preparations by the Combination of Amastatin, Captopril and Phosphoramidon

Toyokazu Hiranuma, Kayoko Iwao, Ken Kitamura, Teruhiko Matsumiya and Tetsuo Oka
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 769-774;

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OtherANALGESIA AND DRUGS OF ABUSE

Almost Complete Protection from [Met5]-Enkephalin-Arg6-Gly7-Leu8(Met-enk-RGL) Hydrolysis in Membrane Preparations by the Combination of Amastatin, Captopril and Phosphoramidon

Toyokazu Hiranuma, Kayoko Iwao, Ken Kitamura, Teruhiko Matsumiya and Tetsuo Oka
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 769-774;
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