HIGH-VALENT Cr, Mn, AND Fe SPECIES - Oxidation of Amino Acids, Peptides, and Proteins: Kinetics and Mechanism - page 292

effects on the thioredoxin reductase (TrxR)/Trx/Prx systems. The study per-
formed on human bronchial epithelial cells (BEAS-2B) showed that the treat-
ment of Cr(VI) resulted in inhibition of TrxR and aconitase, and a number of
reducing equivalents in TrxR determined the oxidation of the thioredoxins in
the BEAS-2B cells [112].
6.1.4.10 NADPH/NADP. The reduction of Cr(VI) by nicotinamide adenine
dinculeotides (NAD(P)H/NAD(P) + ) results in Cr(V), evidenced by EPR mea-
surements [113, 114]. The stabilization of Cr(V) at pH ≥ 7 occurs through the
cis -1,2-diolato moiety of the ribose ring [114]. Details of the mechanism are
still unknown. However, the studies with the NAD(P)H model compound,
10-methyl-9,10-dihydroacridine, under acidic conditions demonstrated the for-
mation of Cr(V), Cr(IV), and organic radical intermediates [115]. The stabili-
zation of Cr(V) could not be achieved due to the acidic conditions of the
experiments.
6.1.4.11 Nitric Oxide Synthase (NOS). The formation of the Cr(V) species
from the Cr(VI)/NOS has been examined by the EPR technique [116]. This
reaction may thus be involved in the cytotoxic and vascular effects of Cr(VI)
pollution. Significantly, the formation of NO from NOS did not preclude the
reduction of Cr(VI) by the enzyme. The reduction of Cr(VI) was independent
of calcium/calmodulin at the reductase domain.
6.1.5 Mechanism
The mechanism of chromium carcinogenicity is not fully understood, but
numerous studies support the genotoxicity and the mutagenicity of Cr(VI) in
vitro and in vivo [44, 83, 86, 87, 92, 96, 98, 117-130]. Figure 6.7 shows the poten-
tial steps of molecular mechanisms that may occur in Cr(VI) carcinogenesis.
Cr(VI) can penetrate cell walls and undergoes intracellular reduction pro-
cesses to produce Cr(V), Cr(IV), and Cr(III) species. Because of the structural
similarity of CrO 2− to physiological SO 2− and phosphate ions, Cr(VI) can enter
into cells via nonspecific anion channels where it can metabolically reduce to
Cr(V), Cr(IV), and Cr(III) to induce a wide range of genomic DNA damage,
which ultimately leads to the inhibition of DNA replication. As discussed in
the previous section, the reduced substrates include Cys, lipoic acid, GSH,
ascorbate, fructose, ribose, NAD(P)H, and hydrogen peroxide. Some redox
proteins are also active in the reduction of Cr(VI). These include heme pro-
teins (cytochrome P450 and hemoglobin) and NADPH-dependent flavoen-
zymes (GSH reductase and NADPH-cytochrome P450 reductase).
In addition to Cr(V) and Cr(IV) species, superoxide anions, hydroxyl radi-
cals, and free radicals have also been suggested in the metabolism of Cr(VI).
It is possible the hydroxyl radical is produced from the Fenton-like reaction
of Cr(IV) and Cr(V) [131, 132]. Electron spin resonance (ESR) techniques in
conjunction with spin trapping agents, 5,5-dimethyl-1-pyrroline-N-oxide