Naranmandura Hua, Suzuki Kazuo T
Graduate School of Pharmaceutical Sciences, Chiba University, Chuo, Chiba 260-8675, Japan.
Toxicol Appl Pharmacol. 2008 Mar 15;227(3):390-9. doi: 10.1016/j.taap.2007.11.008. Epub 2007 Nov 21.
The bladder and skin are the primary targets for arsenic-induced carcinogenicity in mammals. Thioarsenicals dimethylmonothioarsinic (DMMTA(V)) and dimethyldithioarsinic (DMDTA(V)) acids are common urinary metabolites, the former being much more toxic than non-thiolated dimethylarsinic acid (DMA(V)) and comparable to dimethylarsinous acid (DMAIII) in epidermoid cells, suggesting that the metabolic production of thioarsenicals may be a risk factor for the development of cancer in these organs. To reveal their production sites (tissues/body fluids), we examined the uptake and transformation of the four dimethylated arsenicals by incubation with rat and human red blood cells (RBCs). Although DMA(V) and DMDTA(V) were not taken up by either type of RBCs, DMAIII and DMMTA(V) were taken up by both (more efficiently by rat ones), though DMMTA(V) was taken up slowly, and then the arsenic transformed into DMDTA(V) was excreted from both types of animal RBCs. On the other hand, although DMA(III) taken up rapidly by rat RBCs was retained in the RBCs, that taken up by human RBCs was immediately transformed into DMMTA(V) and then excreted into the incubation medium without being retained in the RBCs. In a separate experiment, arsenic remaining in primary rat hepatocytes after incubation with 1.5 microM DMAIII was recovered from the incubation medium in the forms of DMA(V) and DMMTA(V) in the presence of human RBCs, but not in the presence of rat RBCs (in which the arsenic was bound to hemoglobin). Thus, DMMTA(V) was detected in the medium only in the presence of human RBCs and increased with incubation time. It was proposed that arsenic is excreted from hepatocytes into the bloodstream in the form of DMAIII and then taken up by RBCs in humans, where it is transformed into DMMTA(V) and then excreted again into the bloodstream.
膀胱和皮肤是哺乳动物中砷诱导致癌作用的主要靶器官。硫代砷化合物二甲基一硫代砷酸（DMMTA(V)）和二甲基二硫代砷酸（DMDTA(V)）是常见的尿液代谢产物，前者比非硫醇化的二甲基砷酸（DMA(V)）毒性大得多，在表皮样细胞中与二甲基亚砷酸（DMAIII）相当，这表明硫代砷化合物的代谢产生可能是这些器官发生癌症的一个危险因素。为了揭示它们的产生部位（组织/体液），我们通过与大鼠和人类红细胞（RBCs）孵育来研究四种二甲基化砷化合物的摄取和转化。尽管DMA(V)和DMDTA(V)都未被任何一种类型的RBCs摄取，但DMAIII和DMMTA(V)都能被两种细胞摄取（大鼠细胞摄取效率更高），不过DMMTA(V)摄取缓慢，然后转化为DMDTA(V)的砷从两种动物的RBCs中排出。另一方面，尽管大鼠RBCs快速摄取的DMA(III)保留在RBCs中，但人类RBCs摄取的DMA(III)会立即转化为DMMTA(V)，然后排泄到孵育培养基中，而不会保留在RBCs中。在另一个实验中，在人RBCs存在的情况下，与1.5 microM DMAIII孵育后原代大鼠肝细胞中残留的砷以DMA(V)和DMMTA(V)的形式从孵育培养基中回收，但在大鼠RBCs存在的情况下则没有（其中砷与血红蛋白结合）。因此，仅在人RBCs存在的情况下在培养基中检测到DMMTA(V)，并且其随孵育时间增加。有人提出，砷以DMAIII的形式从肝细胞排泄到血液中，然后在人类中被RBCs摄取，在那里它转化为DMMTA(V)，然后再次排泄到血液中。
