HIGH-VALENT Cr, Mn, AND Fe SPECIES - Oxidation of Amino Acids, Peptides, and Proteins: Kinetics and Mechanism - page 298

complexes with DNA [160-162]. The analysis of oxidized products suggests
the possibility of oxidation at the sugar moiety in an addition to the base.
6.1.7 Genotoxicity and Cytotoxicity
Solubility plays an important role in carcinogenicity, which has recently been
demonstrated in human bronchial cells by performing a comparative study
with four Cr(VI) compounds: sodium chromate, zinc chromate, barium chro-
mate, and lead chromate [163, 164]. Sodium chromate is a soluble compound,
while the others are particulate Cr(VI) compounds. The cytotoxic effect of the
Cr(VI) compounds is shown in Figure 6.10A. It is clear that zinc chromate and
barium chromate were more cytotoxic than sodium chromate and lead chro-
mate. The results of genotoxicity experiments are presented in Figure 6.10B.
The formation of γ-H2AX foci suggests the levels of DNA damage were
similar for all three particulate chromates. Zinc chromate was more clasto-
genic than all the other Cr(VI) compounds. Furthermore, there was no differ-
ence in the induction of DNA double-strand breaks for any of the compounds.
It is possible that the zinc ion may be involved in the repairing of DNA, result-
ing in a difference in the carcinogenic potency of zinc chromate over other
chromium compounds [163]. An EPR study was also conducted to understand
the mechanism of cytotoxicity of different chromates using human lung epi-
thelian cells (BEAS-2B). Two Cr(V) EPR signals were observed in the incuba-
tion of cells with sodium chromate. Of the two signals, only one signal was thio
dependent, and both signals were largely NAD(P)H dependent. Both EPR
signals were also seen with zinc chromates. The use of lead chromate did not
give any EPR signal. The most sensitive cells in the clonogenic assays were
with sodium chromate and zinc chromate, while lead chromate was much less
sensitive. A scheme was given to explain the signals in the EPR experiments
(Fig. 6.11). This scheme is consistent with the role of reducing substrates in the
generation of Cr(V) complexes as intermediates before converting to Cr(III)
complexes, which were also detected in the cells.
Cellular resistance took place in the Cr(VI)-induced early stage of carcino-
genesis, although the mechanism remains unclear. The involvement of aber-
rant DNA repair mechanisms, the dysregulation of critical survival signaling
pathways and transcriptional repatterning have been suggested and are shown
in Figure 6.12. In an attempt to repair damaged DNA, a normal cell may go
through a transient checkpoint at the relevant doses of Cr(VI). Although some
cells have DNA repair mechanisms, they lack repair genes such as MLH1 ,
MSH6 , ATM , and PMS2 and cause the development of genomic instability
(Table 6.1) [165-167]. Some cells that are unable to repair the damage may
undergo terminal growth arrest or apoptosis (replicative death). In this process,
some cells may survive by acquiring an intrinsic mechanism(s) of death
resistance.
A summary of death resistance after Cr(VI) exposure is given in Table 6.1
[165-172]. It appears that dysregulated DNA repair mechanisms and/or