Cytotoxic Effects of Hexavalent and Trivalent Chromium on Mammalian Cells In Vitro

Levis, Angelo Gino; Bianchi, Vera; Tamino, Gianni; Pegoraro, Bruna

doi:10.1038/bjc.1978.58

Cited by 105 publications

(43 citation statements)

References 27 publications

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“…A COMPARISON of the cytotoxic and cytogenetic effects of Cr6+ (as potassium dichromate) and Cr3+ (as chromium chloride) on mammalian cell cultures was carried out in our laboratory, and showed quite different mechanisms of action, on the basis of their effects on the physicochemical properties of nucleic acids (Tamino, 1977), the uptake of nucleosides and nucleic acid synthesis (Levis et al, 1978a, b;Bianchi et al, 1979), the mitotic cycle (Majone, 1977) and the frequencies of chromosome aberrations and sister chromatid exchanges (Majone & Majone & Rensi, 1979). The study of the cytotoxic and clastogenic action of chromium on mammalian cells grown in vitro has been extended here to 11 watersoluble compounds of Cr6+ and Cr3+.…”

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Cytotoxic and clastogenic effects of soluble chromium compounds on mammalian cell cultures

Levis¹,

Majone²

1979

Br J Cancer

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Summary.-The inhibition of cell growth, the reduction of cell survival and the induction of chromosome aberrations and of sister chromatid exchange (SCE) have been determined in cultured hamster cell lines (BHK and CHO) treated with 11 water-soluble compounds of hexavalent and trivalent chromium.All Cr6+ compounds inhibit growth of BHK cells and reduce survival of CHO cells to levels comparable to those obtained only after exposure to 100-1000 times higher Cr3+ concentrations. The cytotoxicity curves obtained with the different Cr6+ compounds are almost overlapping, whereas marked differences of activity are noticeable among Cr3+ compounds. Giant cells are obtained after exposure to Cr6+ and Cr3+ compounds, as shown by the rise of DNA and RNA per cell, and are due to the blockage of the cell cycle without sudden inhibition of macromolecular syntheses. Both Cr6+ and Cr3+ compounds are able to induce chromosome aberrations, whereas Cr3+ is absolutely incapable of inducing SCE, only Cr6+ being active. The frequency of chromosome aberrations is increased about 10-fold after exposure to 1-0 jug/ml Cr6+, whereas it is only doubled after treatment with up to 150 jug/ml Cr3+. On the other hand, in spite of the sensitivity of CHO cells to the induction of SCE by mitomycin C, the frequency of SCE hardly doubles after exposure to Cr6+ compounds.The present data confirm that Cr6+ compounds are characterized by a marked cytotoxicity and clastogenic action on mammalian cell cultures and show that Cr3+ compounds, though cytotoxic only at extremely high concentrations and not increasing the frequency of SCE, are not completely without cytogenetic effect, as they are able to induce chromosome aberrations.

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Cytotoxic and clastogenic effects of soluble chromium compounds on mammalian cell cultures

Levis¹,

Majone²

1979

Br J Cancer

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“…Actually, trivalent Cr salts are not mutagenic in bacteria (Venitt and Levy, 1974;Nishioka, 1975); nevertheless Cr acetate (Hueper, 1961), chromite (Hueper, 1958;Payne, 1960) and basic Cr sulphate (Furst and Haro, Accepted 24 November 1976 1969) certainly are carcinogenic, and Cr chloride interacts with nucleic acids purified in vitro (Huff et at., 1964), interferes with macromolecular syntheses and modifies some physico-chemical properties of nucleic acids in cultured mammalian cells (Levis et al, 1976).…”

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“…(Levis et al, 1975) (Levis et al, 1975); radioactivity was determined by a Packard Tri-Carb 2425 scintillation counter and DNA was measured by UV absorption at 268 nm using a Hitachi Perkin-Elmer 124 spectrophotometer. The ratios between radioactivity counts and DNA amounts (specific radioactivities) are referred to as "specific activities".…”

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“…But after the amounts of hexavalent and trivalent Cr are determined, both in the solutions used for treatment and inside the cells, and after the biological actions of K2Cr2O7 and of CrCl3, a trivalent chromium salt, are compared (Levis et al, 1976), it becomes clear that the stimulation of [13H]TdR uptake is due to the reduction of hexavalent chromium on the plasma membrane. Moreover, such reduction appears to be necessary for the penetration of active Cr complexes into the cell.…”

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“…On the other hand, the present data indicate that DNA replication is strongly inhibited by 10-4 M K2Cr2O7 and that its recovery depends on the conditions and duration of treatment as well as on the concentrations of dichromate. DNA synthesis inhibition represents the primary effect of reduced trivalent Cr inside the cell, while RNA and protein syntheses are only secondarily inhibited (Levis et al, 1976).…”

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Effects of potassium dichromate on DNA synthesis in hamster fibroblasts

Levis¹,

Buttignol²

1977

Br J Cancer

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Dna polymerase arrest by adducted trivalent chromium

Bridgewater

Manning

Woo

et al. 1994

Molecular Carcinogenesis

114

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Carcinogenic chromium (Cr6+) enters cells via the sulfate transport system and undergoes intracellular reduction to trivalent chromium, which strongly adducts to DNA. In this study, the effect of adducted trivalent chromium on in vitro DNA synthesis was analyzed with a polymerase-arrest assay in which prematurely terminated replication products were separated on a DNA sequencing gel. A synthetic DNA replication template was treated with increasing concentrations of chromium(III) chloride. The two lowest chromium doses used resulted in biologically relevant adduct levels (6 and 21 adducts per 1,000 DNA nucleotides) comparable with those measured in nuclear matrix DNA from cells treated with a 50% cytotoxic dose of sodium chromate in vivo. In vitro replication of the chromium-treated template DNA using the Sequenase version 2.0 T7 DNA polymerase (United States Biochemical Corp., Cleveland, OH) resulted in dose-dependent polymerase arrest beginning at the lowest adduct levels analyzed. The pattern of polymerase arrest remained consistent as chromium adduct levels increased, with the most intense arrest sites occurring 1 base upstream of guanine residues on the template strand. Replication by the DNA polymerase I large (Klenow) fragment as well as by unmodified T7 DNA polymerase also resulted in similar chromium-induced polymerase arrest. Interstrand cross-linking between complementary strands was detected in template DNA containing 62, 111, and 223 chromium adducts per 1,000 DNA nucleotides but not in template containing 6 or 21 adducts per 1,000 DNA nucleotides, in which arrest nevertheless did occur. Low-level, dose-dependent interstrand cross-linking between primer and template DNA, however, was detectable even at the lowest chromium dose analyzed. Since only 9% of chromium adducts resulted in polymerase arrest in this system, we hypothesized that arrest occurred when the enzyme encountered chromium-mediated interstrand DNA-DNA cross-links between either the template and a separate DNA molecule or the template and its complementary strand in the same molecule. These results suggest that the obstruction of DNA replication by chromium-mediated DNA-DNA cross-links is a potential mechanism of chromium-induced genotoxicity in vivo.

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Cytotoxic Effects of Hexavalent and Trivalent Chromium on Mammalian Cells In Vitro

Cited by 105 publications

References 27 publications

Cytotoxic and clastogenic effects of soluble chromium compounds on mammalian cell cultures

Cytotoxic and clastogenic effects of soluble chromium compounds on mammalian cell cultures

Effects of potassium dichromate on DNA synthesis in hamster fibroblasts

Dna polymerase arrest by adducted trivalent chromium

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