QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.059410v1 308/2/658    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hagrman, D. Articles by Souid, A.-K. Search for Related Content PubMed PubMed Citation Articles by Hagrman, D. Articles by Souid, A.-K.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Kinetic Study on the Reactions of Platinum Drugs with Glutathione

Department of Pediatrics, Upstate Medical University, State University of New York, Syracuse, New York (D.H., A.-K.S.); and Department of Chemistry, Syracuse University, Syracuse, New York (J.G.)

The binding of platinum (Pt) drugs (oxaliplatin, carboplatin, and cisplatin) to glutathione (GSH, 6.75 mM) was investigated at 37°C in Hepes (100 mM, pH 7.4) or Tris-NO₃ (60 mM, pH 7.4) buffer and NaCl (4.62, 6.63, or 7.82 mM). The conditions were chosen to mimic passage of clinical concentrations of the drugs (135 µM) through the cytosol. The reactions were monitored by UV-absorption spectroscopy, high-performance liquid chromatography (HPLC), and atomic absorption spectroscopy. The initial rates, detected by UV absorbance, were similar for oxaliplatin and cisplatin reacting with GSH and were more than 5-fold faster than for carboplatin reacting with GSH. The Pt contents in HPLC eluates corresponding to unbound drug decreased exponentially with time, confirming that the reactions were first order in [Pt drug] and allowing determination of the pseudo first-order rate constants (k₁). The second-order rate constants (k₂) were calculated as k₁ divided by [GSH]. The k₂ value for oxaliplatin reacting with GSH was 3.8 x 10^–2 M^–1 s^–1, for cisplatin reacting with GSH 2.7 x 10^–2 M^–1 s^–1, and for carboplatin reacting with GSH 1.2 x 10^–3 M^–1 s^–1 (32-fold slower than that of oxaliplatin and 23-fold slower than that of cisplatin). These results demonstrate an influence of ligands surrounding the Pt coordination sphere on the reactivity of Pt²⁺ with GSH.

Address correspondence to: Dr. Abdul-Kader Souid, Department of Pediatrics, Upstate Medical University, State University of New York, 750 East Adams St., Syracuse, NY 13210. E-mail: souida{at}upstate.edu

This article has been cited by other articles:

				C. Peklak-Scott, P. K. Smitherman, A. J. Townsend, and C. S. Morrow Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin Mol. Cancer Ther., October 1, 2008; 7(10): 3247 - 3255. [Abstract] [Full Text] [PDF]

				N. Ragunathan, J. Dairou, B. Pluvinage, M. Martins, E. Petit, N. Janel, J.-M. Dupret, and F. Rodrigues-Lima Identification of the Xenobiotic-Metabolizing Enzyme Arylamine N-Acetyltransferase 1 as a New Target of Cisplatin in Breast Cancer Cells: Molecular and Cellular Mechanisms of Inhibition Mol. Pharmacol., June 1, 2008; 73(6): 1761 - 1768. [Abstract] [Full Text] [PDF]

				D. Gholam, S. Giacchetti, C. Brezault-Bonnet, M. Bouchahda, D. Hauteville, R. Adam, B. Ducot, O. Ghemard, F. Kustlinger, C. Jasmin, et al. Chronomodulated Irinotecan, Oxaliplatin, and Leucovorin-Modulated 5-Fluorouracil as Ambulatory Salvage Therapy in Patients with Irinotecan- and Oxaliplatin-Resistant Metastatic Colorectal Cancer Oncologist, November 1, 2006; 11(10): 1072 - 1080. [Abstract] [Full Text] [PDF]

				J. Peng, R. Mandal, M. Sawyer, and X.-F. Li Characterization of Intact Hemoglobin and Oxaliplatin Interaction by Nanoelectrospray Ionization Tandem Mass Spectrometry Clin. Chem., December 1, 2005; 51(12): 2274 - 2281. [Abstract] [Full Text] [PDF]