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Cr(IV) causes activation of nuclear transcription factor-kappa B, DNA strand breaks and dG hydroxylation via free radical reactions.

Authors
Shi-X; Ding-M; Ye-J; Wang-S; Leonard-SS; Zang-L; Castranova-V; Vallyathan-V; Chiu-A; Dalal-N; Liu-K
Source
J Inorg Biochem 1999 May; 75(1):37-44
NIOSHTIC No.
20025399
Abstract
Electrophoretic mobility shift, DNA strand breakage assays and electron spin resonance (ESR) spin trapping were used to investigate the activation of nuclear transcription factor (NF)-kappa B, DNA strand breakage and 2'-deoxyguanosine hydroxylation induced by Cr(IV), as well the role of free radical reactions in these processes. Incubation of synthesized Cr(IV)-glutathione complex with cultured Jurkat cells resulted in activation of DNA binding activity of NF-kappa B. Cr(VI) is also able to induce NF-kappa B activation through Cr(V) and Cr(IV) intermediates generated during the reduction of Cr(VI) by the cells. Cr(III) did not cause observable NF-kappa B activation due to its inability to cross cell membranes. Cr(IV)-induced NF-kappa B activation is dose-dependent. Catalase inhibited the activation while superoxide dismutase enhanced it. The metal chelator, deferoxamine, and hydroxyl (.OH) radical scavengers, sodium formate and aspirin, also inhibited the NF-kappa B activation. Electrophoretic assays using lambda Hind III linear DNA showed that, in the presence of H2O2, Cr(IV) is capable of causing DNA strand breaks. Deferoxamine, sodium formate and aspirin inhibited the DNA strand breaks. HPLC measurements also show that .OH radical generated by the Cr(IV)-mediated reaction with H2O2 was capable of causing 2'-deoxyguanosine (dG) hydroxylation to generate 8-hydroxyguanosine (8-OHdG). The relative magnitude of 8-OHdG formation correlated with the generation of .OH radicals. ESR spin trapping measurements showed that reaction of Cr(IV) with H2O2 generated .OH radicals, which were inhibited by deferoxamine, sodium formate and aspirin. The results show that Cr(IV) can cause NF-kappa B activation, DNA strand breaks and dG hydroxylation through .OH radical-initiated reactions. This reactive chromium intermediate may play an important role in the mechanism of Cr(VI)-induced carcinogenesis. The results also suggest that the Cr(IV)-glutathione complex may be used as a model compound to study the role of Cr(IV) in Cr(VI) carcinogenicity.
Keywords
Hydroxylation-reactions; Carcinogenesis; Carcinogenicity; Carcinogens; Models; Mutation; Mutagenesis; Gene-mutation
CODEN
JIBIDJ
Publication Date
19990530
Document Type
Journal Article
Email Address
xas0@cdc.gov
Fiscal Year
1999
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
0162-0134
NIOSH Division
HELD
Source Name
Journal of Inorganic Biochemistry
State
WV; DC; FL; NH
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