Inhibition of human excision DNA repair by inorganic arsenic and the co-mutagenic effect in V79 Chinese hamster cells

Abstract

We investigated the lethal, UV killing-potentiating and repair-inhibiting effects of trivalent arsenic trioxide (As 2O 3) and pentavalent sodium arsenate (Na 2HAsO 4) in normal human and xeroderma pigmentosum (XP) fibroblasts. The presence of As 2O 3 for 24 h after UV irradiation inhibited the thymine dimer excision from the DNA of normal and XP variant cells and thus the subsequent unscheduled DNA synthesis (UDS): excision inhibitions were partial, 30–40%, at a physiological dose of 1 μg/ml and 100% at a supralethal dose of 5 μg/ml. Correspondingly, As 2O 3 also potentiated the lethal effect of UV on excision-proficient normal and XP variant cells in a concentration-dependent manner, but not on excision-defective XP group A cells. Na 2HAsO 4 (As 5+) was approximately an order of magnitude less effective in preventing all the above repair events than As 2O 3 (As 3+) which is highly affinic to SH-containing proteins. The above results provide the first evidence that arsenic inhibits the excision of pyrimidine dimers. Partially repair-suppressing small doses of As 2O 3 (0.5 μg/ml) and Na 2HAsO 4 (5 μg/ml) enhanced co-mutagenically the UV induction of 6-thioguanine-resistant mutations of V79 Chinese hamster cells. Thus, such a repair inhibition may be one of the basic mechanisms for the co-mutagenicity and presumably co-carcinogenicity of arsenic. XP group A and variant strains showed a unique higher sensitivity to As 2O 3 and Na 2HAsO 4 killing by a yet unidentified mechanism.