Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics.
To elucidate if the metabolic methylation participates in the induction of inorganic arsenic-responsible genetic damage, arsenite (ARS) and its methylated metabolites, methanearsonic acid (MMAA) and dimethylarsinic acid (DMAA), were comparatively assayed for the induction of DNA damage by determining DNA repair synthesis using polymerization inhibitors such as aphidicolin (aph) and hydroxyurea (HU). When human alveolar epithelial type II (L-132) cells in culture were exposed to either one of these three arsenic compounds, DNA single-strand breaks resulting from the inhibition of repair polymerization were remarkably produced by exposure to DMAA at 5 to 100 microM, while not by that to ARS and MMAA even at 100 microM. Furthermore, a bromodeoxyuridine (BrdrU)-photolysis assay indicated that the induction of DNA repair synthesis was observed only in the case of exposure to DMAA. When L-132 cells were exposed to 100 microM MMAA in the presence of 10 mM S-adenosyl-L-methionine (SAM), which is a well-known methyl-group donor in metabolic methylation of arsenics, DNA repair synthesis was induced along with an increase in the amount of dimethylarsenic in the cells. These results indicate that metabolic methylation of inorganic arsenics to dimethylarsenics is predominantly involved in the induction of DNA damage.
Yamanaka
K
K
Department of Biochemical Toxicology, Nihon University College of Pharmacy, Chiba, Japan.
Hayashi
H
H
Tachikawa
M
M
Kato
K
K
Hasegawa
A
A
Oku
N
N
Okada
S
S
D020261:Arsenic Poisoning; D001152:Arsenicals; D002101:Cacodylic Acid / Q000633:toxicity*; D002460:Cell Line; D002849:Chromatography, Gas; D004260:DNA Repair; D006801:Humans; D008745:Methylation; D009153:Mutagens / Q000633:toxicity*
D001152:Arsenicals; D009153:Mutagens; D002101:Cacodylic Acid; C020300:monomethylarsonic acid