Elsevier

Biochemical Pharmacology

Volume 37, Issue 15, 1 August 1988, Pages 2939-2948
Biochemical Pharmacology

Hydrolysis of the four stereoisomers of soman catalyzed by liver homogenate and plasma from rat, guinea pig and marmoset, and by human plasma

https://doi.org/10.1016/0006-2952(88)90279-1Get rights and content

Abstract

Stereoselective hydrolysis at pH 7.5 and 37° of C(±)P(±)-soman by liver homogenate and plasma from rat, guinea pig and marmoset, and by human plasma is studied by using the four single stereoisomers. The fast hydrolysis of the C(±)P(+)-isomers is monitored titrimetrically, whereas the decay of the much slower reacting C(±)P(−)-isomers is followed by gas Chromatographie determination of the residual concentration. Values of Km and Vmax are evaluated for the enzymatic hydrolysis of the two relatively nontoxic C(±)P(+)-isomers. The plasma enzymes have a high affinity for these isomers (Km : 0.01−0.04 M); the Km values of the liver enzymes vary between 0.04 and 0.7 mM. Except for rat liver homogenate, only first-order rate constants can be obtained for catalyzed hydrolysis (kc) of the highly toxic C(±)P(−)-isomers: most measurements with C(±)P(−)-isomer concentrations 0.3 mM are complicated by epimerization to C(+-)P(+)-isomers, which may conceal enzyme saturation with the C(±)P(-)-isomers. The first-order rate constants of catalyzed hydrolysis (Vmax/Km or kc) by all liver homogenates and plasmata decrease in the order: C(+)P(+)- C(−)P(+)- ;C(−)P(−)- C(+)P(−)-soman. The highest P(+)-/P(−)-stereoselectivity is found for rat plasma. Rat liver homogenate is more potent than the other liver homogenates in catalyzing the hydrolysis of both the C(±)P(+)- and the C(±)P(−)-isomers. Rat plasma shows the highest activity for degradation of the C(±)P(+)-isomers, but is approximately as active as marmoset and human plasma for degradation of the C(±)P(−)-isomers.

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This research was supported by Research Grant DAMD 17-85-G-5004 from U.S. Army Medical Research and Development Command.

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