METABOLIC METHYLATION IS A POSSIBLE GENOTOXICITY-ENHANCING PROCESS OFINORGANIC ARSENICS

To elucidate if the metabolic methylation participates in the inductio n of inorganic arsenic-responsible genetic damage, arsenite (ARS) and its methylated metabolites, methanearsonic acid (MMAA) and dimethylars inic acid (DMAA), were comparatively assayed for the induction of DNA damage by determining DNA repair synthesis using polymerization inhibi tors such as aphidicolin (aph) and hydroxyurea (HU). When human alveol ar epithelial type II (L-132) cells in culture were exposed to either one of these three arsenic compounds, DNA single-strand breaks resulti ng from the inhibition of repair polymerization were remarkably produc ed by exposure to DMAA at 5 to 100 mu M, while not by that to ARS and MMAA even at 100 mu M. Furthermore, a bromodeoxyuridine (BrdrU)-photol ysis assay indicated that the induction of DNA repair synthesis was ob served only in the case of exposure to DMAA. When L-132 cells were exp osed to 100 mu M MMAA in the presence of 10 mM S-adenosyl-L-methionine (SAM), which is a well-known methyl-group donor in metabolic methylat ion of arsenics, DNA repair synthesis was induced along with an increa se in the amount of dimethylarsenic in the cells. These results indica te that metabolic methylation of inorganic arsenics to dimethylarsenic s is predominantly involved in the induction of DNA damage. (C) 1997 E lsevier Science B.V.