Reactions of Chromium(VI/V/IV) with Bis(O-ethyl-l-cysteinato-N,S)zinc(II):  A Model for the Action of Carcinogenic Chromium on Zinc-Finger Proteins¹

Abstract

The reactions of Cr(VI/V/IV) with a model thiolato complex [Zn(SR)2] (RSH = O-ethyl-l-cysteine), resembling a tetrahedral (2S,2N) Zn(II) binding site in zinc-finger proteins, have been studied in comparison with those of the free ligand. The stability of [Zn(SR)2] in aqueous solutions with pH 6−11 (25 °C, Ar-saturated) has been established by CD spectroscopy. Stoichiometries and products of the reactions of [Zn(SR)2] or RSH with [CrVIO4]2- or [CrVO(ehba)2]- (ehba = 2-ethyl-2-hydroxybutanoato(2−)) at pH 6.5−8.5 (25 °C, Ar) were studied by UV−vis and CD spectroscopies and by electrospray mass spectrometry. Disulfide (RSSR) is the only detectable oxidation product of both [Zn(SR)2] and RSH. In the case of RSH, relatively stable Cr(III) complexes, [CrIII(SR)3]0 and [CrIII(SR)2]+, are also formed and subsequently hydrolyzed to [CrIII(Cys)2]-. This is the first observation of a Cr(III)-facilitated hydrolysis of a cysteine ester. Ascorbate promotes the oxidation of [Zn(SR)2] by [CrVIO4]2-; this reaction leads to formation of RSSR and of the Cr(III)−thiolato complexes. Kinetics of the reactions of [Zn(SR)2] or RSH with [CrVIO4]2-, [CrVO(ehba)2]-, or [CrIVO(qa)(qaH)]- (qa = quinato(2−) = (1R,3R,4R,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylato(2−)) at pH 7.40 (25 °C, Ar) were studied by conventional and stopped-flow UV−vis spectrophotometry and by global kinetic analysis. Complexes of Cr(V) and Cr(IV) rapidly react with both the reductants, and reactions of Cr(V) pass through the Cr(IV) intermediates. By contrast with the reaction with RSH, the reaction of [CrVO(ehba)2]- with [Zn(SR)2] is not accompanied by a significant O2 consumption (measured by an oxygen electrode), suggesting the ability of [Zn(SR)2] to inhibit free radical reactions, similar to that of zinc metallothioneins. The mechanism of [Zn(SR)2] oxidation by Cr(VI/V/IV), including intramolecular formation of a disulfide bond, has been proposed. Implications of the results to the Cr(VI)-induced carcinogenesis and to the biological activity of Cr(III) are discussed.

Kinetics and mechanism of a macrocyclic chromium(III) complex oxidation to chromium(IV) by hexacyanoferrate(III) in strongly alkaline media

“…Thus, chromium(III), is stable as the hexaaquachromium(III) complex in acidic media, where chromium(II) and chromium(VI) species, such as hexaaquachromium(II) and dichromate, behave as reducing and oxidizing agents, respectively. In weakly basic solution, chromium(III) initially forms a dark green gel of Cr(OH) 3 , which is soluble in excess base, forming chromate(III), frequently written as [Cr(OH) 6 ] 3) , but essentially a poorly defined complex system of monomers and polymeric species. Such solutions are easily oxidized and chromium(VI) is the stable oxidation product in the form of CrO 4 2) .…”

“…Such solutions are easily oxidized and chromium(VI) is the stable oxidation product in the form of CrO 4 2) . Solutions of chromium species at the intermediate oxidation states, IV and V, have been studied intensively in recent years especially because of their suspected biological importance including attempts to understand the mutagenic and carcinogenic effects of chromium(VI) [3][4][5][6][7][8][9]. Chromium(IV) and chromium(V) species coordinated with water and deprotonated water ligands are unstable in aqueous solution irrespective of the acidity.…”

“…The main goal of the present study was to examine the kinetics of oxidation of chromium(III) to chromium(IV) in alkaline solutions using the much simpler oxidant [Fe(CN) 6 ] 3) , which is an established mild one-electron oxidant [25]. Additionally, a stoichiometric, kinetic and e.p.r.…”

Kinetics and mechanism of a trans-tetraazamacrocyclic chromium(III) complex oxidation by hexacyanoferrate(III) in strongly alkaline media

“…Recently some results on the structure and reactivity of chromium(IV) and chromium(V) complexes have been published [8][9][10][11].…”

Apoptosis of Lymphocytes in the Presence of Cr(V) Complexes: Role in Cr(VI)-Induced Toxicity

“…The toxicity profile of higher valent chromium may depend not only on the oxidation state but also on the different radical intermediates, which may be produced during the redox processes. A pathway involving the production of organic radicals and further activation by molecular oxygen in the reactions of Cr(VI/V/IV) with cellular reductants, leading to the formation of oxidation products, as a probable cause in genotoxicity of chromium has been suggested by Lay and co-workers (45)(46)(47). In the presence of Cr(VI), Cr(V) and Cr(IV), employing thiols as model reductants, redox processes involving the formation of thiyl as well as RSO 2 • radicals leading to the initiation of a chain reaction, has been invoked.…”