Formation and reactivity of chromium(V)-thiolato complexes: a model for the intracellular reactions of carcinogenic chromium(VI) with biological thiols.

The nature of the long-lived EPR-active Cr(V) species observed in cells and biological fluids exposed to carcinogenic Cr(VI) has been definitively assigned from detailed kinetic and spectroscopic analyses of a model reaction of Cr(VI) with p-bromobenzenethiol (RSH) in the presence or absence of cyclic 1,2-diols (LH(2)) in aprotic or mixed solvents. The first definitive structures for Cr(V) complexes with a monodentate thiolato ligand, Cr(V)O(SR)(4) (g(iso) = 1.9960, A(iso) = 14.7 x 10(-4) cm(-1)), Cr(V)OL(SR)(2) (g(iso) = 1.9854, A(iso) = (15.8-16.2) x 10(-4) cm(-1)) and Cr(V)(O)(2)(SR)(2) (g(iso) = 1.9828, A(iso) = 6.8 x 10(-4) cm(-1)) were assigned by EPR spectroscopy and electrospray mass spectrometry. The unusually low A(iso) ((53)Cr) value for the latter species is consistent with its rare four-coordinate, bis-oxido structure. The Cr(V)OL(SR)(2) species are responsible for the transient g(iso) approximately 1.986 EPR signals observed in living cells and animals treated with Cr(VI) (where RSH and LH(2) are biological thiols and 1,2-diols, respectively). For the first time, concentrations of Cr(V) intermediates formed during the reduction of Cr(VI) were determined by quantitative EPR spectroscopy, and a detailed reaction mechanism was proposed on the basis of stochastic simulations of the kinetic curves for Cr(V) species. A key feature of the proposed mechanism is the regeneration of Cr(V) species in the presence of Cr(VI) through the formation of organic free radicals, followed by the rapid reactions of the formed radicals with Cr(VI). The concentration of Cr(V) grows rapidly at the beginning of the reaction, reaches a steady-state level, and then drops sharply once Cr(VI) is spent. Similar mechanisms are likely to operate during the reduction of Cr(VI) in biological environment rich in reactive C-H bonds, including the oxidative DNA damage by Cr(V) intermediates.