Styblo M, Del Razo L M, Vega L, Germolec D R, LeCluyse E L, Hamilton G A, Reed W, Wang C, Cullen W R, Thomas D J
Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, 27599, USA.
Arch Toxicol. 2000 Aug;74(6):289-99. doi: 10.1007/s002040000134.
Biomethylation is considered a major detoxification pathway for inorganic arsenicals (iAs). According to the postulated metabolic scheme, the methylation of iAs yields methylated metabolites in which arsenic is present in both pentavalent and trivalent forms. Pentavalent mono- and dimethylated arsenicals are less acutely toxic than iAs. However, little is known about the toxicity of trivalent methylated species. In the work reported here the toxicities of iAs and trivalent and pentavalent methylated arsenicals were examined in cultured human cells derived from tissues that are considered a major site for iAs methylation (liver) or targets for carcinogenic effects associated with exposure to iAs (skin, urinary bladder, and lung). To characterize the role of methylation in the protection against toxicity of arsenicals, the capacities of cells to produce methylated metabolites were also examined. In addition to human cells, primary rat hepatocytes were used as methylating controls. Among the arsenicals examined, trivalent monomethylated species were the most cytotoxic in all cell types. Trivalent dimethylated arsenicals were at least as cytotoxic as trivalent iAs (arsenite) for most cell types. Pentavalent arsenicals were significantly less cytotoxic than their trivalent analogs. Among the cell types examined, primary rat hepatocytes exhibited the greatest methylation capacity for iAs followed by primary human hepatocytes, epidermal keratinocytes, and bronchial epithelial cells. Cells derived from human bladder did not methylate iAs. There was no apparent correlation between susceptibility of cells to arsenic toxicity and their capacity to methylate iAs. These results suggest that (1) trivalent methylated arsenicals, intermediary products of arsenic methylation, may significantly contribute to the adverse effects associated with exposure to iAs, and (2) high methylation capacity does not protect cells from the acute toxicity of trivalent arsenicals.
生物甲基化被认为是无机砷化合物（iAs）的主要解毒途径。根据推测的代谢方案，iAs的甲基化产生甲基化代谢产物，其中砷以五价和三价形式存在。五价单甲基和二甲基砷化合物的急性毒性低于iAs。然而，关于三价甲基化物种的毒性知之甚少。在本文报道的研究中，研究了iAs以及三价和五价甲基化砷化合物在源自被认为是iAs甲基化主要部位（肝脏）的组织或与接触iAs相关的致癌作用靶点（皮肤、膀胱和肺）的培养人类细胞中的毒性。为了表征甲基化在抵御砷化合物毒性中的作用，还研究了细胞产生甲基化代谢产物的能力。除了人类细胞外，原代大鼠肝细胞被用作甲基化对照。在所研究的砷化合物中，三价单甲基化物种在所有细胞类型中细胞毒性最大。对于大多数细胞类型，三价二甲基化砷化合物的细胞毒性至少与三价iAs（亚砷酸盐）一样大。五价砷化合物的细胞毒性明显低于其三价类似物。在所研究的细胞类型中，原代大鼠肝细胞对iAs的甲基化能力最强，其次是原代人类肝细胞、表皮角质形成细胞和支气管上皮细胞。源自人膀胱的细胞不会使iAs甲基化。细胞对砷毒性的敏感性与其使iAs甲基化的能力之间没有明显的相关性。这些结果表明：（1）砷甲基化的中间产物三价甲基化砷化合物可能对与接触iAs相关的不良反应有显著贡献；（2）高甲基化能力并不能保护细胞免受三价砷化合物的急性毒性。
