STUDY OF INORGANIC ARSENIC METHYLATION BY RAT-LIVER INVITRO - RELEVANCE FOR THE INTERPRETATION OF OBSERVATIONS IN MAN
STUDY OF INORGANIC ARSENIC METHYLATION BY RAT-LIVER INVITRO - RELEVANCE FOR THE INTERPRETATION OF OBSERVATIONS IN MAN
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DOI：
10.1007/bf00343122
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发表时间：
1985-01-01
影响因子：
6.1
通讯作者：
LAUWERYS, R
中科院分区：
文献类型：
--
作者：
BUCHET, JP;LAUWERYS, R
无机砷的生物转化在体外大鼠肝脏导致生产的单甲基化和二甲基化的砷衍生物，测量通过无火焰原子吸收作为单甲基胂酸（MMA）和二甲基胂酸（DMA），分别。甲基化活性定位于胞质溶胶中，并且仅接受As 3+作为底物。其最适pH值介于7.5和8.0之间，还原型谷胱甘肽（10-2 M）是完全活性所必需的。S-腺苷甲硫氨酸是必需的甲基供体，类可啉衍生物协同作用。过量的底物和汞离子的加入防止了二甲基化砷衍生物的形成，而不影响单甲基化化合物的形成。显然，在哺乳动物中，无机砷的甲基化涉及两种不同的酶活性。先前在人体中的观察结果（Buchet et al. 1981 B，1984）和本研究的结果表明，DMA的产生是MMA前体随后甲基化的结果，尽管还不能最终排除代谢物也是通过2种完全独立的途径产生的可能性。MMA和DMA生产的动力学提供了一个解释的观察结果，在志愿者给予越来越多的As 3+，DMA的尿排泄水平关闭速度比MMA和急性中毒的患者As 3+，几天可能会过去之前DMA成为优势代谢物。在给予标准剂量的As 3+的肝病患者中发现，MMA生产的减少与DMA合成的增加相关，这可能是由于肝细胞对As 3+的摄取减少。
The biotransformation of inorganic arsenic by rat liver in vitro leads to the production of a monomethylated and a dimethylated arsenic derivative, measured by flameless atomic absorption as monomethylarsonic (MMA) and dimethylarsinic (DMA) acids, respectively. The methylating activity is localized in the cytosol and accepts only As3+ as substrate. Its optimum pH lies between 7.5 and 8.0, and reduced glutathione (10-2 M) is required for full activity. S-Adenosylmethionine is the essential methyl group donor and corrinoid derivatives act synergistically. An excess of substrate and the addition of mercuric ions prevent the formation of the dimethylated arsenic derivative without affecting that of the monomethylated compound. Evidently, 2 different enzymatic activities are involved in the methylation of inorganic arsenic in mammals. Previous observations in man (Buchet et al. 1981 b, 1984) and the results of the present study suggest that DMA production results from the subsequent methylation of the MMA precursor, although the possibility that metabolites are also produced by 2 completely independent pathways cannot yet be conclusively rejected. The kinetics of MMA and DMA production provide an explanation for the observations that in volunteers given increasing amounts of As3+, the urinary excretion of DMA levels off faster than that of MMA and in patients acutely intoxicated with As3+, several days may elapse before DMA becomes the preponderant metabolite. The reduction of MMA production associated with an increased synthesis of DMA found in patients with liver diseases given a standard dose of As3+ might be due to a reduction of As3+ uptake by the liver cells.