Styblo M, Del Razo L M, LeCluyse E L, Hamilton G A, Wang C, Cullen W R, Thomas D J
Department of Pediatrics, School of Medicine, and Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Chem Res Toxicol. 1999 Jul;12(7):560-5. doi: 10.1021/tx990050l.
The liver is considered a major site for methylation of inorganic arsenic (iAs). However, there is little data on the capacity of human liver to methylate iAs. This work examined the metabolism of arsenite (iAs(III)), arsenate (iAs(V)), methylarsine oxide (MAs(III)O), methylarsonic acid (MAs(V)), dimethylarsinous acid (DMAs(III)), and dimethylarsinic acid (DMAs(V)) in primary cultures of normal human hepatocytes. Primary rat hepatocytes were used as methylating controls. iAs(III) and MAs(III)O were metabolized more extensively than iAs(V) and MAs(V) by either cell type. Neither human nor rat hepatocytes metabolized DMAs(III) or DMAs(V). Methylation of iAs(III) by human hepatocytes yielded methylarsenic (MAs) and dimethylarsenic (DMAs) species; MAs(III)O was converted to DMAs. The total methylation yield (MAs and DMAs) increased over the range of 0.1 to 4 microM iAs(III). However, DMAs production was inhibited by iAs(III) in a concentration-dependent manner, and the DMAs/MAs ratio decreased. iAs(III) (10 and 20 microM) inhibited both methylation reactions. Inhibition of DMAs synthesis resulted in accumulation of iAs and MAs in human hepatocytes, suggesting that dimethylation is required for iAs clearance from cells. Methylation capacities of human hepatocytes obtained from four donors ranged from 3.1 to 35.7 pmol of iAs(III) per 10(6) cells per hour and were substantially lower than the methylation capacity of rat hepatocytes (387 pmol of iAs(III) per 10(6) cells per hour). The maximal methylation rates for either rat or human hepatocytes were attained between 0.4 and 4 microM iAs(III). In summary, (i) human hepatocytes methylate iAs, (ii) the capacities for iAs methylation vary among individuals and are saturable, and (iii) moderate concentrations of iAs inhibit DMAs synthesis, resulting in an accumulation of iAs and MAs in cells.
肝脏被认为是无机砷（iAs）甲基化的主要场所。然而，关于人类肝脏甲基化iAs能力的数据却很少。这项研究检测了正常人肝细胞原代培养物中亚砷酸盐（iAs(III)）、砷酸盐（iAs(V)）、甲基氧化砷（MAs(III)O）、甲基砷酸（MAs(V)）、二甲基亚砷酸（DMAs(III)）和二甲基砷酸（DMAs(V)）的代谢情况。原代大鼠肝细胞用作甲基化对照。两种细胞类型对iAs(III)和MAs(III)O的代谢都比iAs(V)和MAs(V)更广泛。人肝细胞和大鼠肝细胞均不代谢DMAs(III)或DMAs(V)。人肝细胞对iAs(III)的甲基化产生甲基砷（MAs）和二甲基砷（DMAs）物种；MAs(III)O转化为DMAs。在0.1至4 microM的iAs(III)范围内，总甲基化产率（MAs和DMAs）增加。然而，iAs(III)以浓度依赖性方式抑制DMAs的产生，并且DMAs/MAs比值降低。iAs(III)（10和20 microM）抑制两种甲基化反应。DMAs合成的抑制导致人肝细胞中iAs和MAs的积累，这表明二甲基化是iAs从细胞中清除所必需的。从四名供体获得的人肝细胞的甲基化能力范围为每10^6个细胞每小时3.
