Jo William J, Loguinov Alex, Wintz Henri, Chang Michelle, Smith Allan H, Kalman Dave, Zhang Luoping, Smith Martyn T, Vulpe Chris D
Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, California 94720, USA.
Toxicol Sci. 2009 Oct;111(2):424-36. doi: 10.1093/toxsci/kfp162. Epub 2009 Jul 27.
Arsenic is a human toxin and carcinogen commonly found as a contaminant in drinking water. Arsenite (As(III)) is the most toxic inorganic form, but recent evidence indicates that the metabolite monomethylarsonous acid (MMA(III)) is even more toxic. We have used a chemical genomics approach to identify the genes that modulate the cellular toxicity of MMA(III) and As(III) in the yeast Saccharomyces cerevisiae. Functional profiling using homozygous deletion mutants provided evidence of the requirement of highly conserved biological processes in the response against both arsenicals including tubulin folding, DNA double-strand break repair, and chromatin modification. At the equitoxic doses of 150 microM MMA(III) and 300 microM As(III), genes related to glutathione metabolism were essential only for resistance to the former, suggesting a higher potency of MMA(III) to disrupt glutathione metabolism than As(III). Treatments with MMA(III) induced a significant increase in glutathione levels in the wild-type strain, which correlated to the requirement of genes from the sulfur and methionine metabolic pathways and was consistent with the induction of oxidative stress. Based on the relative sensitivity of deletion strains deficient in GSH metabolism and tubulin folding processes, oxidative stress appeared to be the primary mechanism of MMA(III) toxicity whereas secondary to tubulin disruption in the case of As(III). Many of the identified yeast genes have orthologs in humans that could potentially modulate arsenic toxicity in a similar manner as their yeast counterparts.
砷是一种人体毒素和致癌物，通常作为饮用水中的污染物被发现。亚砷酸盐（As(III)）是毒性最强的无机形式，但最近的证据表明，代谢产物一甲基亚砷酸（MMA(III)）毒性更强。我们采用化学基因组学方法，在酿酒酵母中鉴定出调节MMA(III)和As(III)细胞毒性的基因。利用纯合缺失突变体进行功能分析，结果表明，在应对这两种砷化合物时，包括微管蛋白折叠、DNA双链断裂修复和染色质修饰在内的高度保守的生物学过程是必需的。在150 microM MMA(III)和300 microM As(III)的等毒性剂量下，与谷胱甘肽代谢相关的基因仅对前者的抗性至关重要，这表明MMA(III)比As(III)对谷胱甘肽代谢的破坏作用更强。用MMA(III)处理野生型菌株后，谷胱甘肽水平显著升高，这与硫和甲硫氨酸代谢途径中基因的需求相关，并且与氧化应激的诱导一致。基于缺乏谷胱甘肽代谢和微管蛋白折叠过程的缺失菌株的相对敏感性，氧化应激似乎是MMA(III)毒性的主要机制，而在As(III)的情况下，氧化应激是微管蛋白破坏的次要机制。许多已鉴定的酵母基因在人类中有直系同源基因，它们可能以与其酵母对应物类似的方式调节砷的毒性。
