Is there a role for reactive oxygen species in the mechanism of chromium(VI) carcinogenesis?

Standeven, Andrew M.; Wetterhahn, Karen E.

doi:10.1021/tx00024a003

Cited by 115 publications

(64 citation statements)

References 94 publications

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“…Alternatively, DNA single-strand breaks or DNA-protein cross-links, although repaired prior to the onset of cell death, may cause the induction of a signal that induces cells to undergo apoptosis. A further possibility is that free radicals, produced as a result of the intracellular reduction of hexavalent chromium (8,(42)(43)(44), may trigger apoptosis in affected cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis.

Manning

Blankenship

Wise

et al. 1994

Environ Health Perspect

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Hexavalent chromium (Cr) compounds are respiratory carcinogens in humans and animals. Treatment of Chinese hamster ovary cells with 150 and 300 pM sodium chromate (Na2CrO4) for 2 hr decreased colony-forming efficiency by 46 and 92%, respectively. These treatments induced dosedependent internucleosomal fragmentation of cellular DNA beyond 24 hr after chromate treatment. This fragmentation pattern is characteristic of apoptosis as a mechanism of cell death. These treatments also induced an immediate inhibition of macromolecular synthesis and delayed progression of cells through S-phase of the cell cycle. Cell growth (as evidenced by DNA synthesis) was inhibited for at least 4 days and transcription remained suppressed for at least 32 hr. Many of the cells that did progress to metaphase exhibited chromosome damage. Chromate caused the dose-dependent formation of DNA single-strand breaks and DNA-protein cross-links, but these were repaired 8 and 24 hr after removal of the treatment, respectively. In contrast, Cr-DNA adducts (up to 1/100 base-pairs) were extremely resistant to repair and were still detectable even 5 days after treatment. Compared with other regions of the genome, DNA-protein cross-links and Cr adducts were preferentially associated with the nuclear matrix DNA of treated cells, which was 4.5-fold enriched in actively transcribed genes. Chromium adducts, formed on DNA in vitro at a similar level to that detected in nuclear matrix DNA, arrested the progression of a DNA polymerase in a sequence-specific manner, possibly through the formation of DNA-DNA cross-links. Total RNA and mRNA synthesis and induction of expression of the inducible GRP78 gene were suppressed in a concentration-and time-dependent manner by chromate. The effects of chromate on GRP78 induction correlated most closely with the presence of DNA-protein cross-links but suppression of total RNA and mRNA synthesis correlated with the presence of DNA-Cr adducts in cells. These results suggest that the persistent Cr-DNA adducts may be responsible for the protracted cell cycle delay and transcriptional inhibition caused by chromate. Escape from apoptosis may be one of the steps involved in chromate-induced carcinogenesis. -Environ Health Perspect 102(Suppl 3): 159-167 (1994).

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Section: Discussionmentioning

confidence: 99%

Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis.

Manning

Blankenship

Wise

et al. 1994

Environ Health Perspect

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“…During this reduction, reactive Cr species [Cr(V) and/or Cr(IV)] are formed. These can directly cause oxidative-like damage (Sugden, 1999;Sugden et al, 2001) or they can generate ROS via redox cycling (Tsapakos et al, 1983;Standeven and Wetterhahn, 1991;Shi and Dalal, 1992;Dillon et al, 1998;Shi et al, 1999a;Shi et al, 1999b;Borthiry et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

2008

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Hexavalent chromium [Cr(VI)] species such as chromates are cytotoxic. Inhalational exposure is a primary concern in many Cr-related industries and their immediate environments, and bronchial epithelial cells are directly exposed to inhaled Cr(VI). Chromates are readily taken up by cells and are reduced to reactive Cr species which may also result in the generation of reactive oxygen species (ROS). The thioredoxin (Trx) system has a key role in the maintenance of cellular thiol redox balance and is essential for cell survival. Cells normally maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. Redox western blots were used to assess the redox status of the thioredoxins in normal human bronchial epithelial cells (BEAS-2B) incubated with soluble Na 2 CrO 4 or insoluble ZnCrO 4 for different periods of time. Both chromates caused a doseand time-dependent oxidation of Trx2 and Trx1. Trx2 was more susceptible in that it could all be converted to the oxidized form, whereas a small amount of reduced Trx1 remained even after prolonged treatment with higher Cr concentrations. Only one of the dithiols, presumably the active site, of Trx1 was oxidized by Cr(VI). Cr(VI) did not cause significant GSH depletion or oxidation indicating that Trx oxidation does not result from a general oxidation of cellular thiols. With purified Trx and thioredoxin reductase (TrxR) in vitro, Cr(VI) also resulted in Trx oxidation. It was determined that purified TrxR has pronounced Cr(VI) reducing activity, so competition for electron flow from TrxR might impair its ability to reduce Trx. The in vitro data also suggested some direct redox interaction between Cr(VI) and Trx. The ability of Cr(VI) to cause Trx oxidation in cells could contribute to its cytotoxic effects, and could have important implications for cell survival, redoxsensitive cell signaling, and the cells' tolerance of other oxidant insults.

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“…Electron donors that transfer three electrons in a single step have not been identified in biological systems, so the reduction of Cr(VI) to Cr(III) must proceed stepwise through Cr(V) and/or Cr(IV) which are reactive Cr intermediates. These reactive Cr intermediates, and their potential to generate reactive oxygen species, are likely important components in the toxicity resulting from Cr(VI) exposure [17,[19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Reductive activation of hexavalent chromium by human lung epithelial cells: Generation of Cr(V) and Cr(V)-thiol species

Borthiry

Antholine

Myers

et al. 2008

Journal of Inorganic Biochemistry

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Chromium(VI) compounds (e.g. chromates) are cytotoxic, mutagenic, and potentially carcinogenic. The reduction of Cr(VI) can yield reactive intermediates such as Cr(V) and reactive oxygen species. Bronchial epithelial cells are the primary site of pulmonary exposure to inhaled Cr(VI) and are the primary cells from which Cr(VI)-associated human cancers arise. BEAS-2B cells were used here as a model of normal human bronchial epithelium for studies on the reductive activation of Cr(VI). Cells incubated with Na 2 CrO 4 exhibited two Cr(V) ESR signals, g = 1.979 and 1.985, which persisted for at least one hour. The g = 1.979 signal is similar to that generated in vitro by human microsomes and by proteoliposomes containing P450 reductase and cytochrome b 5 . Unlike many cells in culture, these cells continued to express P450 reductase and cytochrome b 5 . Studies with the non-selective thiol oxidant diamide indicated that the g = 1.985 signal was thiol-dependent whereas the g = 1.979 signal was not. Pretreatment with phenazine methosulfate eliminated both Cr(V) signals suggesting that Cr(V) generation is largely NAD(P)H-dependent. ESR spectra indicated that a portion of the Cr (VI) was rapidly reduced to Cr(III). Cells incubated with an insoluble chromate, ZnCrO 4 , also generated both Cr(V) signals, whereas Cr(V) was not detected with insoluble PbCrO 4 . In clonogenic assays, the cells were very sensitive to Na 2 CrO 4 and ZnCrO 4 , but considerably less sensitive to PbCrO 4 .

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Is there a role for reactive oxygen species in the mechanism of chromium(VI) carcinogenesis?

Cited by 115 publications

References 94 publications

Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis.

Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis.

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

Reductive activation of hexavalent chromium by human lung epithelial cells: Generation of Cr(V) and Cr(V)-thiol species

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