In Vitro Plasmid DNA Cleavage by Chromium(V) and -(IV) 2-Hydroxycarboxylato Complexes

Abstract

The ability of relatively stable Cr(V) and Cr(IV) complexes with 2-hydroxycarboxylato ligands [2-ethyl-2-hydroxybutanoate(2-) = ehba; (1R,3R,4R,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylate(2-) = quinate = qa] to induce single-strand breaks in plasmid DNA has been studied under a wide range of reaction conditions. The Cr(V) complex, Na[CrVO(ehba)2], causes substantial DNA cleavage at pH 4.0-8.0 [[Cr(V)]0 = 0.010-0.75 mM, phosphate buffer, and 37 degrees C]. The DNA cleavage is inhibited by the presence of excess ligand, by exclusion of O2, or by addition of organic compounds, such as alcohols, carboxylic acids, or DMSO, but it is not affected by traces of catalytic metals [Fe(III) or Cu(II)] or by addition of catalase. The Cr(IV)-qa complexes, unlike the Cr(V) complexes, are able to cleave DNA in the presence of the ligand in a large excess [[Cr(IV)]0 = 0.50 mM, [qa] = 20-100 mM, pH 3.5-6.0, and 37 degrees C]. This is the first direct evidence for DNA cleavage induced by well-characterized Cr(IV) complexes. The proposed mechanism for DNA cleavage includes the following: (i) partial aquation of the bis-chelated Cr(V) and -(IV) complexes with the formation of reactive monochelated forms, (ii) binding of the Cr(V) and -(IV) monochelates to the phosphate backbone of DNA, (iii) one- or two-electron oxidations at the deoxyribose moieties of DNA by Cr(V) and -(IV), and (iv) cleavage of the resulting DNA radicals or cations with or without participation of O2. The patterns of DNA damage by Cr(V) and -(IV) can include strand breaks, generation of abasic sites, and the formation of Cr(III)-DNA complexes.

Effects of Neutral, Cationic, and Anionic Chromium Ascorbate Complexes on Isolated Human Mitochondrial and Genomic DNA

“…Effect of the nature of the chromium species on human mitochondrial and genomic DNA Although most of the Cr(III) complexes were reportedly non-mutagenic, there are studies demonstrating that Cr(III) can directly bind to DNA (Cohen et al, 1993;Levina et al, 1999 (Beyersmann and Köster, 1987).…”

“…Model complexes of Cr(V) and Cr(IV) possess DNA cleavage properties under a wide range of reaction conditions (Bose et al, 1998;Levina et al, 1999). Rao et al studied the biological activities of Cr(III) compounds with biogenic ligands, such as saccharides (Rao et al, 1994;Kaiwar et al, 1995;Sreedhara et al, 1997) and SH-containing molecules (Kaiwar et al, 1996).…”

O impacto do crômio nos sistemas biológicos

“…Além desses exemplos, tem-se os experimentos envolvendo a espectroscopia de luminescência associada com a eletroforese capilar, que forneceram informações pertinentes sobre a natureza e a estereoseletividade enantiomérica das interações de complexos do tipo Cr(diimina) 3 [NaClO 4 ] = 1.0 M, 37 °C, e os experimentos cinéticos estudados em condições similares 17 , mostraram que a interação direta com os grupos fosfatos é provavelmente a primeira etapa no mecanismo de clivagem do ADN em solução aquosa e pH neutro. Posteriormente, experimentos realizados com complexos de Cr(IV) e ácido quínico, demonstraram que os mesmos são capazes de quebrar a molécula de ADN na presença de excesso do ácido na faixa de pH 3,5-6,0 a 37°C 51 . Tal resultado representa a primeira evidência direta de que complexos de Cr(IV) podem também induzir a clivagem do ADN.…”

Hard X-ray microprobe studies of chromium(VI)-treated V79 Chinese hamster lung cells: intracellular mapping of the biotransformation products of a chromium carcinogen

“…There have been numerous mechanisms proposed for the intracellular metabolism of Cr(VI) that ultimately leads to Cr-induced cancers [1,2,3,4,5]. Some postulated mechanisms include the involvement of organic or hydroxyl radicals produced by the intracellular reductions of Cr(VI) [3,6,7,8].…”

“…Some postulated mechanisms include the involvement of organic or hydroxyl radicals produced by the intracellular reductions of Cr(VI) [3,6,7,8]. Other proposed mechanisms involve direct Cr reactions of highly active Cr(IV) or Cr(V) species with DNA or RNA to produce strand breaks [1,2,9,10], Cr-DNA binding that results in disruption of the replication process [5,11], or the formation of DNA-protein cross-links by Cr(III) species [12,13,14]. Chromium metabolism has been investigated by studies of specific reactions of Cr with cellular molecules (namely DNA, RNA, GSH, ascorbic acid, a-tocopherol, etc.)…”