Effects of trivalent and hexavalent chromium on the physicochemical properties of mammalian cell nucleic acids and synthetic polynucleotides

Arrest of replication by mammalian DNA polymerases α and β caused by chromium-DNA lesions

“…Hexavalent chromium is believed to enter cells by active transport via the sulfate anion transport system [10,11] and is reduced intracellularly to trivalent chromium primarily by ascorbate [12,13]. Although trivalent chromium is not actively transported into cells, it can bind to DNA and form adducts and DNA interstrand crosslinks in cell-free systems [14][15][16], and it is believed to function similarly in vivo after reduction [17][18][19]. In addition, several intermediates of the hexavalent to trivalent chromium reduction can also interact with and bind to DNA [20].…”

Cytotoxic and clastogenic effects of soluble and insoluble compounds containing hexavalent and trivalent chromium

“…It can be seen (Table IX) (Sirover & Loeb, 1976;Tkeshelashvili et al, 1980), point mutations in bacteria (Venitt & Levy, 1974;Nishioka, 1975;Green et al, 1976;Petrilli & De Flora, 1978b;Lofroth, 1978;Nakamuro et al, 1978;Nestmann et al, 1979;Kada et al, 1980;Kanematsu et al, 1980;De Flora, 1981), yeast (Bonatti et al, 1976) and mammalian cells (Newbold et al, 1-979); and gene conversion (Bonatti et al, 1976) and mitotic reconmbination (Nestmann et al, 1979) in yeasts; chromosomal aberrations (Tsuda & Kato, 1977;Nakamuro et al, 1978;Newbold et al, 1979;Umeda & Nishimura, 1979;Douglas et al, 1980); SCE Majone & Rensi, 1979;MacRae et al, 1979;Douglas et al, 1980); DNA damage Tamino & Peretta, 1980;Douglas et al, 1980;Tamino et al, 1981); DNA repair synthesis ; morphological transformation (Fradkin et al, 1975;Tsuda & Kato, 1977; and enhancement of viral transformation in cultured mammalian cells; increased frequency of micronuclei and chromosomal aberrations in cells of rodents treated in vivo (Wild, 1978) as well as in lymphocytes of professionally exposed workers (Bigaliev et al, 1977). Cr(VI) compounds gave positive results in the mouse "spot" test (Knudsen, 1980) and transformed Syrian hamster cells when injected into pregnant hamsters , thus indicating that they are also transplacental mutagens.…”

“…On the contrary, Cr(III) salts are usually inactive in mutagenicity tests (Venitt & Levy, 1974;Nishioka, 1975;Petrilli & De Flora, 1978b;Kada et al, 1980;Kanematsu et al, 1980;De Flora, 1981) except in systems involving a direct interaction with DNA purified in vitro, such as damage shown by the alteration of its physico-chemical properties (Tamino & Peretta, 1980;Tamino et al, 1981) and increased error frequency during replication (Sirover & Loeb, 1976;Tkeshelashvili 1980). The only frequent cytogenetic effect in mammalian cells treated in vitro with Cr(III) compounds is the increase of chromosome aberrations (Nakamuro et al, 1978;Levis & Mlajone, 1979; see also the present data), but it is obtained with doses much higher than the active Cr(VI) concentrations, and could be related to an indirect effect produced by such extreme conditions, e.g.…”

“…The present experiments (Table VI) Whereas the cytotoxic action of Cr (VI) has been attributed to the oxidation of biological targets placed mainly on the cell membrane (Levis et al, 1978a,b;Bianchi et al, 1980;Luciani et al, 1979), its genetic activity could depend on the interaction of intracellularly reduced Cr(III) with specific targets on the DNA molecule (Levis et al, 1978a,b;Norseth, 1979;Langard, 1980;Petrilli & De Flora, 1-980;Bianchi et al, 1980;Leonard & Lauwerys, 1980). Interactions with nucleic acids, giving changes of their physicochemical and biochemical properties which could be relevant to the production of genetic changes, have been shown to occur both when purified nucleic acids are treated in vitro with Cr(III) compounds (Sirover & Loeb, 1976;Tamino & Peretta, 1980;Tkeshelashvili et al, 1980: Tamino et al, 1981 and when cells are treated with Cr(VI) compounds Douglas et al, 1980;Tamino et al, 1981). Owing to the stability of Cr(III) chelates and coordination complexes and to their very low exchange rate with biological ligands (Mertz, 1969;Norseth, 1979;Langard, 1980;Petrilli & De Flora, 1980), the crucial site for the expression of Cr(VI) (carcino) genetic activity should be where Cr(VI) is converted to Cr(III).…”

“…Markedly different cytotoxic and cytogenetic activities of water-soluble Cr(VI), as potassium dichromate, and Cr(III), as chromium chloride, were shown in our laboratory, with mammalian cell cultures, on the basis of their effects on the physicochemical properties of nucleic acids (Tamino & Peretta, 1980;Tamino et al, 1981), nucleoside uptake and nucleic acid synthesis (Levis et al, 1978a, b;Bianchi et al, 1979Bianchi et al, , 1980, the functions of plasmamembrane enzymes (Luciani et al, 1979), the cell-division cycle (Majone & Rensi, 1979), the induction of chromosome aberrations and sister-chromatid exchanges . A screening of the cytotoxic and clastogenic action of 11 water-soluble compounds of Cr(VI) and Cr(III) has been also carried out and is extended here by another 10 very soluble, barely soluble and highly insoluble compounds containing Cr(VI) and Cr(III), among which are several industrial pigments the carcinogenicity of which in the rat (Maltoni, 1976) and mutagenicity in bacteria (Petrilli & De Flora, 1978a, b;De Flora, 1981) have already been established (Table I).…”