Kobayashi Yayoi, Hirano Seishiro
Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
Toxicol Appl Pharmacol. 2008 Oct 1;232(1):33-40. doi: 10.1016/j.taap.2008.06.003. Epub 2008 Jun 21.
Trivalent arsenicals such as arsenite (iAs(III)), monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) are more toxic than analogous pentavalent compounds such as arsenate (iAs(V)), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)). It has been reported that arsenic-glutathione (As-GSH) complexes such as arsenic triglutathione (ATG) and methylarsenic diglutathione (MADG) are major metabolites in rat bile following intravenous administration of iAs(III). Recently, we have shown that both ATG and MADG are unstable and easily hydrolyzed to iAs(III) and MMA(III), respectively, and that MMA(III) is oxidized to MMA(V) in bile. In the present study we report the effects of H(2)O(2) and GSH on the stability of As-GSH complexes in rat bile. Male SD rats were injected intravenously with saline or iAs(III) at a dose of 0.2 or 2.0 mg As/kg body weight, and bile fluid was collected on ice for 30 min. To estimate the stability of As-GSH complexes in bile, ATG or MADG was added to untreated, heat-treated, catalase-treated, or dialyzed bile, and then incubated at 37 degrees C for 10 min. Concentrations of biliary H(2)O(2) and GSH in the higher dose group were 12.6- and 4.5-times higher than the control value, respectively. Exogenously added trivalent arsenicals were oxidized to pentavalent arsenicals in the bile depending on the biliary concentration of H(2)O(2). Both catalase and dialysis prevented oxidation of trivalent arsenicals to the corresponding pentavalent compounds. Exogenously added GSH stabilized As-GSH complexes in bile. These results suggest that H(2)O(2) converts trivalent arsenicals to less toxic pentavalent arsenicals, whereas GSH prevents hydrolysis of As-GSH complexes and the generation of unconjugated toxic trivalent arsenicals.
三价砷化合物，如亚砷酸盐（iAs(III)）、一甲基亚砷酸（MMA(III)）和二甲基亚砷酸（DMA(III)），比类似的五价化合物，如砷酸盐（iAs(V)）、一甲基砷酸（MMA(V)）和二甲基砷酸（DMA(V)）毒性更强。据报道，静脉注射iAs(III)后，大鼠胆汁中的主要代谢产物是砷-谷胱甘肽（As-GSH）复合物，如三谷胱甘肽砷（ATG）和二谷胱甘肽甲基砷（MADG）。最近，我们发现ATG和MADG都不稳定，容易分别水解为iAs(III)和MMA(III)，并且MMA(III)在胆汁中被氧化为MMA(V)。在本研究中，我们报告了H(2)O(2)和GSH对大鼠胆汁中As-GSH复合物稳定性的影响。雄性SD大鼠静脉注射生理盐水或剂量为0.2或2.0 mg As/kg体重的iAs(III)，并在冰上收集胆汁30分钟。为了评估胆汁中As-GSH复合物的稳定性，将ATG或MADG添加到未处理、热处理、过氧化氢酶处理或透析的胆汁中，然后在37℃孵育10分钟。高剂量组胆汁中H(2)O(2)和GSH的浓度分别比对照值高12.6倍和4.5倍。根据胆汁中H(2)O(2)的浓度，外源添加的三价砷化合物在胆汁中被氧化为五价砷化合物。过氧化氢酶和透析都能防止三价砷化合物氧化为相应的五价化合物。外源添加的GSH可稳定胆汁中的As-GSH复合物。这些结果表明，H(2)O(2)将三价砷化合物转化为毒性较小的五价砷化合物，而GSH可防止As-GSH复合物水解和未结合的有毒三价砷化合物的生成。
