Abstract | BACKGROUND: METHODS: GCP activity was first characterized in both human skin and rat paw pads. GCP activity was then monitored in both rodent paw pads and sciatic nerve from the same animals following peripheral administration of various doses of GCP inhibitor. Significant differences among measurements were determined using two-tailed distribution, equal variance student's t test. RESULTS: We describe for the first time, a direct and quantifiable assay to evaluate GCP enzymatic activity in human skin biopsy samples. In addition, we show that GCP activity in skin is responsive to pharmacological manipulation; GCP activity in rodent paws was inhibited in a dose response manner following peripheral administration of a potent and selective GCP inhibitor. Inhibition of GCP activity in rat paw pads was shown to correlate to inhibition of GCP activity in peripheral nerve. CONCLUSION: Monitoring GCP activity in human skin after administration of GCP inhibitors could be readily used as PD marker in the clinical development of GCP inhibitors. Enzymatic activity provides a simple and direct measurement of GCP activity from tissue samples easily assessable in human subjects.
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Authors | Camilo Rojas, Marigo Stathis, Michael Polydefkis, Michelle A Rudek, Ming Zhao, Gigi J Ebenezer, Barbara S Slusher |
Journal | Journal of translational medicine
(J Transl Med)
Vol. 9
Pg. 27
(Mar 09 2011)
ISSN: 1479-5876 [Electronic] England |
PMID | 21388540
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-(phosphonomethyl)pentanedioic acid
- Biomarkers
- Organophosphorus Compounds
- Carboxypeptidases
- glutamate carboxypeptidase
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Topics |
- Animals
- Biomarkers
(metabolism)
- Biopsy
- Carboxypeptidases
(antagonists & inhibitors, metabolism)
- Chromatography, Liquid
- Dose-Response Relationship, Drug
- Humans
- Male
- Mass Spectrometry
- Organophosphorus Compounds
(administration & dosage, analysis, pharmacology)
- Rats
- Rats, Wistar
- Sciatic Nerve
(drug effects, enzymology)
- Skin
(drug effects, enzymology, pathology)
- Time Factors
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