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Research ArticleArticle

In Vivo Inhibition of Peptidylglycine-α-Hydroxylating Monooxygenase by 4-Phenyl-3-Butenoic Acid

Gregory P. Mueller, William J. Driscoll and Betty A. Eipper
Journal of Pharmacology and Experimental Therapeutics September 1999, 290 (3) 1331-1336;
Gregory P. Mueller
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William J. Driscoll
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Betty A. Eipper
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Abstract

Peptidylglycine-α-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyzes the first and rate-limiting reaction in the two-step process that α-amidates neural and endocrine peptides. The substrate analog 4-phenyl-3-butenoic acid (PBA) was shown in vitro to selectively inhibit PHM without affecting the activity of peptidyl-α-hydroxyglycine α-amidating lyase, the enzyme that mediates the second reaction in α-amidation. Inhibition of PHM activity by PBA lowered the Vmax of the enzyme without altering its Km. Administration of PBA in vivo profoundly inhibited serum PHM activity in a dose- and time-related fashion. Maximal reductions to less than 5% of control levels were observed 3 h after a single administration (500 mg/kg). Inhibition of serum PHM activity by PBA was short-lived, being fully reversed by 24 h postinjection. PHM activity in cardiac atrium, hypothalamus, and anterior and neurointermediate lobes of the pituitary were also decreased by PBA treatment but to a lesser extent than with serum. Inhibition of PHM activity by PBA was not cumulative over time when assessed 24 h after the last of 10 daily injections (500 mg/kg). The role of protein synthesis in maintaining PHM activity in blood was demonstrated by treatment with cycloheximide, which reduced serum PHM activity and retarded the recovery of PHM activity after PBA administration. It is concluded that the metabolism and/or clearance of PBA is rapid and that de novo protein synthesis has an important role in mediating the rapid restoration of PHM activity after PBA administration.

Footnotes

  • Send reprint requests to: Dr. Gregory P. Mueller, Department of Physiology and Program in Neuroscience, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799. E-mail: gmueller{at}usuhs.mil

  • ↵1 This work was supported by U.S. Public Health Service Grant NS-34173 and US UHS Grant RO-7644 (to G.P.M.).

  • ↵2 Current address: Departments of Neuroscience and Physiology, Wood Basic Science Building, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.

  • Abbreviations:
    PHM
    peptidylglycine-α-hydroxylating monooxygenase
    PAL
    peptidyl-α-hydroxyglycine α-amidating lyase
    PAM
    peptidylglycine-α-amidating monooxygenase
    PBA
    4-phenyl-3-butenoic acid
    NIL
    neurointermediate pituitary lobes
    MES
    2-(N-morpholino)ethanesulfonic acid
    • Received December 7, 1998.
    • Accepted June 2, 1999.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 290 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 3
1 Sep 1999
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Research ArticleArticle

In Vivo Inhibition of Peptidylglycine-α-Hydroxylating Monooxygenase by 4-Phenyl-3-Butenoic Acid

Gregory P. Mueller, William J. Driscoll and Betty A. Eipper
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1331-1336;

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Research ArticleArticle

In Vivo Inhibition of Peptidylglycine-α-Hydroxylating Monooxygenase by 4-Phenyl-3-Butenoic Acid

Gregory P. Mueller, William J. Driscoll and Betty A. Eipper
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1331-1336;
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