Berkman C E, Ryu S, Quinn D A, Thompson C M
Department of Chemistry, Loyola University of Chicago, Illinois 60626.
Chem Res Toxicol. 1993 Jan-Feb;6(1):28-32. doi: 10.1021/tx00031a004.
Inhibitory (ki), spontaneous (k0), and oxime-mediated reactivation (k(oxime)) reaction kinetics for the four stereoisomers of isomalathion (SPRC,SPSC,RPRC, and RPSC) were determined against rat brain acetylcholinesterase (AChE). (SPRC)-Isomalathion was the most potent anticholinesterase agent and RPSC-isomalathion the least potent with racemic material approximately midway in activity. Following inhibition of rat brain AChE by (SPRC)- or (SPSC)-isomalathion, k0 and k(oxime) values were obtained that were comparable to (SP)-isoparathion methyl, indicating that the same mechanism of inhibition was shared, namely, formation of an O,S-dimethyl phosphorothiolated enzyme. Conversely, no appreciable reactivation occurred with or without oxime following inhibition of rat brain AChE by (RPSC)- or (RPRC)-isomalathion. This observation was not consistent with (RP)-isoparathion methyl, and a switch in inhibition mechanism to the loss of the thiomethyl moiety is suggested. The nonreactivation of rat brain AChE following inhibition by the (RP)-isomalathion stereoisomers is postulated to result from a mechanism involving either a beta-elimination of diethyl fumarate or displacement of the thiosuccinate moiety from the phosphate moiety.
测定了异马拉硫磷（SPRC、SPSC、RPRC和RPSC）的四种立体异构体对大鼠脑乙酰胆碱酯酶（AChE）的抑制（ki）、自发（k0）和肟介导的复活（k(肟)）反应动力学。（SPRC）-异马拉硫磷是最有效的抗胆碱酯酶剂，而RPSC-异马拉硫磷效力最低，外消旋体的活性大致处于中间水平。用（SPRC）-或（SPSC）-异马拉硫磷抑制大鼠脑AChE后，得到的k0和k(肟)值与（SP）-甲基异对硫磷相当，这表明它们具有相同的抑制机制，即形成O,S-二甲基磷酰化硫醇酶。相反，用（RPSC）-或（RPRC）-异马拉硫磷抑制大鼠脑AChE后，无论有无肟，均未发生明显的复活。这一观察结果与（RP）-甲基异对硫磷不一致，提示抑制机制转变为硫甲基部分的丢失。推测（RP）-异马拉硫磷立体异构体抑制后大鼠脑AChE不复活是由于涉及富马酸二乙酯的β-消除或硫代琥珀酸部分从磷酸部分的取代的机制所致。
