TY - JOUR
T1 - Kinetic study of the reaction of cisplatin with thiols
AU - Dabrowiak, James C.
AU - Goodisman, Jerry
AU - Souid, Abdul Kader
PY - 2002/12/1
Y1 - 2002/12/1
N2 - The reactions of cisplatin [cis-diamminedichloroplatinum(II), CDDP] with glutathione (GSH) and drug thiols were investigated at 37°C in 100 mM Tris-NO3, pH ∼7.4, using a clinically relevant concentration of CDDP (33 μM), a large excess of GSH (16.5 mM), and [NaCl] of 4.62 mM. The conditions were designed to mimic passage of CDDP through the cytosol. The reactions were studied by UV-absorption spectroscopy, high-pressure liquid chromatography (HPLC), and atomic absorption spectroscopy. The initial rates, detected by UV absorbance, confirmed that the reactions are first order in [CDDP]. The HPLC peak corresponding to CDDP was analyzed for platinum content by atomic absorption spectroscopy, which decreased exponentially with time, confirming that the reactions are first order in [CDDP] and allowing determination of the pseudo first order rate constants (k1). For reaction of the dichloro form of CDDP with GSH, the k1 value was ∼2.2 × 10-4 s-1 (t1/2 of ∼53 min), giving the second order rate constant value (k2) of ∼1.3 × 10-2 M-1 s-1. Reaction of a mixture of the aquated forms of CDDP with GSH gave a lower k1 value (∼0.9 × 10-4 s-1). Reaction of CDDP with sodium 2-mercaptoethanesulfonate (mesna) gave a k1 value of ∼1.8 × 10-4 s-1 (t1/2 of ∼65 min and k2 of ∼1.1 × 10-2 M-1 s-1). Reaction of CDDP with S-2-(3-aminopropylamino)ethanethiol (WR-1065) gave a k1 value of ∼12.0 × 10-4 s-1 (t1/2 of ∼10 min and k2 of ∼7.3 × 10-2 M-1 s-1). The relatively slow reaction rate of CDDP with GSH is consistent with the efficient DNA platination by CDDP in the presence of millimolar concentration of GSH in the cytosol.
AB - The reactions of cisplatin [cis-diamminedichloroplatinum(II), CDDP] with glutathione (GSH) and drug thiols were investigated at 37°C in 100 mM Tris-NO3, pH ∼7.4, using a clinically relevant concentration of CDDP (33 μM), a large excess of GSH (16.5 mM), and [NaCl] of 4.62 mM. The conditions were designed to mimic passage of CDDP through the cytosol. The reactions were studied by UV-absorption spectroscopy, high-pressure liquid chromatography (HPLC), and atomic absorption spectroscopy. The initial rates, detected by UV absorbance, confirmed that the reactions are first order in [CDDP]. The HPLC peak corresponding to CDDP was analyzed for platinum content by atomic absorption spectroscopy, which decreased exponentially with time, confirming that the reactions are first order in [CDDP] and allowing determination of the pseudo first order rate constants (k1). For reaction of the dichloro form of CDDP with GSH, the k1 value was ∼2.2 × 10-4 s-1 (t1/2 of ∼53 min), giving the second order rate constant value (k2) of ∼1.3 × 10-2 M-1 s-1. Reaction of a mixture of the aquated forms of CDDP with GSH gave a lower k1 value (∼0.9 × 10-4 s-1). Reaction of CDDP with sodium 2-mercaptoethanesulfonate (mesna) gave a k1 value of ∼1.8 × 10-4 s-1 (t1/2 of ∼65 min and k2 of ∼1.1 × 10-2 M-1 s-1). Reaction of CDDP with S-2-(3-aminopropylamino)ethanethiol (WR-1065) gave a k1 value of ∼12.0 × 10-4 s-1 (t1/2 of ∼10 min and k2 of ∼7.3 × 10-2 M-1 s-1). The relatively slow reaction rate of CDDP with GSH is consistent with the efficient DNA platination by CDDP in the presence of millimolar concentration of GSH in the cytosol.
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U2 - 10.1124/dmd.30.12.1378
DO - 10.1124/dmd.30.12.1378
M3 - Article
C2 - 12433807
AN - SCOPUS:0036891973
SN - 0090-9556
VL - 30
SP - 1378
EP - 1384
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 12
ER -