BISMUTH(III) COMPLEXES OF THE TRIPEPTIDE GLUTATHIONE (GAMMA-L-GLU-L-CYS-GLY)

The tripeptide glutathione (gamma-L-Glu-L-Cys-Gly, GSH) is thought to play an important role in the pharmacology of bismuth drugs, but to ou r knowledge no chemical studies of bismuth glutathione complexes have been reported. We report here studies of interactions of the antiulcer compound ranitidine bismuth citrate (1) and [Bi(edta)](-) with glutat hione in aqueous solution and in intact red blood cells by NMR spectro scopy. The deprotonated thiol group is shown to be the strongest bindi ng site for Bi-III, and a complex with the stoichiometry [Bi(GS)(3)] i s formed, as determined by C-13 NMR titrations. A remarkably large low -field shift of approximately 1.37 ppm for the beta-CH2 H-1 NMR resona nces of GSH was observed on binding to Bi-III. The complex [Bi(GS)(3)] is stable over the pH range 2-10 (pH* = pH meter reading in D2O solu tion), A formation constant log K of 29.6+/-0.4 (I = 0.1 M, 298 K) for [Bi(GS)(3)] was determined by displacement of edta by GSH. The rate o f exchange of GSH between free and bound forms is pH-dependent, rangin g from slow exchange (on the H-1 NMR timescale) at low pH (ca. 3 s(-1) at pH 4.0) to intermediate exchange at biological pH (ca. 1500 s(-1)) . Such facile exchange may be important in the transport and delivery of Bi-III in vivo, Spin-echo H-1 NMR showed that 1 reacts with GSH in red cells both in vivo and in vitro. A first-order reaction of 1 with red blood cells was observed in vitro (k = 0.20+/-0.04 h(-1), t(1/2) = 3 h, 310 K), and the rate-determining step appeared to involve the pa ssage of Bi-III through the cell membrane.