Nickel(II) inhibits the repair of O-6-methylguanine in mammalian cells

Nickel compounds are widespread carcinogens, and although only weakly mutag enic, interfere with nucleotide excision repair and with the repair of oxid ative DNA base modifications. In the present study we investigated the effe ct of nickel(II) on the induction and repair of O-6-methylguanine and N7-me thylguanine after treatment with N-methyl-N-nitrosourea (MNU). We applied C hinese hamster ovary cells stably transfected with human O-6-methylguanine- DNA methyl transferase (MGMT) cDNA (CHO-AT), and compared the results with the MGMT-deficient parental cell line. As determined by high-performance li quid chromatography/electrochemical detection (HPLC/ECD), there was a sligh t but mostly not significant reduction in the formation of both types of DN A lesions by MNU in the presence of nickel(II). Although nickel(II) did not markedly affect the repair of N7-methylguanine, it decreased the repair of O-6-methylguanine in a dose-dependent manner, starting at concentrations a s low as 50 mu M While the MGMT protein level was not altered in the presen ce of nickel(II), the MGMT activity was diminished as demonstrated in cell extracts form nickel-treated cells. This repair inhibition was accompanied by an increase in MNU-induced cytotoxicity in nickel-treated CHO-AT cells b ut not in MGMT-deficient control cells. There is strong evidence that O-6-m ethylguanine is involved in tumour formation after exposure to alkylating a gents. Thus, the finding that nickel(II) inhibits the repair of this lesion could be of major importance for risk assessment in case of combined expos ures at work places and in the general environment.