The mechanism of soman detoxification in perfused rat liver

The detoxification of soman (1,2,2-dimethyl-propyl methylphosphonofluoridate) was measured in rat livers, using hemoglobin-free, non-recirculating perfusion in situ. Since the detoxification processes may differ in perivenous and periportal zones of liver parenchyma, soman uptake, stereoselective metabolism and inhibition of esterases were compared in antegrade and retrograde perfusion experiments. At low concentrations of soman (up to about 10 mumol l-1 for 5 min) soman was taken up by the liver nearly quantitatively. About 5% recovery rate in the perfusate corresponded well to the intrahepatic shunt flow. Infusions of higher amounts yielded increasing recovery rates. The racemic infusion medium contained the four isomers of soman, C(-)P(-) to C(+)P(+), in nearly identical amounts, whereas in the effluent perfusate only P(-) isomers were found. Even small amounts of soman (5-120 nmol g-1 liver wet weight) caused significant inhibition of hepatic aliesterase activity. Doses higher than 200 nmol g-1 suppressed esterase activity by more than 90%. No essential differences in soman uptake, stereoselective metabolism or inhibition of esterases were found between antegrade and retrograde perfusion experiments.

show abstract

“…In the effluent only P(-) isomers were detected, which corresponds well to the results of other authors (Sterri et al 1983;Nordgren et al 1984).…”

Section: Discussionsupporting

confidence: 88%

“…The liver exhibits a high capacity of soman detoxification, to an almost quantitative extent at low concentrations (Sterri et al 1980(Sterri et al , 1983, due to its high mainly cytosolic content of phosphorylphosphatases. The esterases, which also bind soman, are distributed in cytosol and the microsomal system.…”

Section: Introductionmentioning

confidence: 99%

Detoxification of soman in the perfused rat liver: Quantitative uptake and stereoisomer metabolism

Wahlländer

Szinicz

1990

Arch Toxicol

View full text Add to dashboard Cite

show abstract

Development of Tolerance to the Toxicity of Xenobiotics

Fonnum¹

2009

General, Applied and Systems Toxicology

View full text Add to dashboard Cite

The development of tolerance to xenobiotics usually involves the inactivation of receptors or the induction of enzymes that bind or inactivate the xenobiotics. This review showns, as the main example, anticholinesterase, the effect of which is modified in several different ways. Tolerance depends on the internalization or inactivation of the muscarinic receptor or the nicotinic receptor. Also mentioned is the interaction of the adenosine receptor with the cholinergic system. Further, the importance of carboxylesterases, butyrylcholinesterase and phosphoric hydrolases in tolerance is discussed. An interesting topic included is the survival of acetylcholinesterase knock‐out animals. Finally the mechanism of tolerance to morphine in the locus coerulus is discussed as an example.

show abstract

Interaction of organophosphorus compounds with carboxylesterases in the rat

Jokanović¹,

Kosanović²,

Maksimović³

1996

Archives of Toxicology

View full text Add to dashboard Cite

Carboxylesterases (CarbE) are involved in detoxication of organophosphorus compounds (OPC) through two mechanisms: hydrolysis of ester bonds in OPC which contain them and binding of OPC at the active site of CarbE which reduces the amount of OPC available for acetylcholinesterase inhibition. This study of the interaction of rat plasma and liver CarbE with dichlorvos, soman and sarin in vitro and in vivo was undertaken in order to contribute to better understanding of the role of CarbE in detoxication of OPC. The results obtained have shown that inhibitory potency (I50) of dichlorvos, sarin and soman towards rat liver CarbE was 0.2 microM, 0.5 microM and 4.5 microM, respectively, for 20-min incubation at 25 degrees C. Second-order rate constants (k(a)) for liver CarbE inhibition were 2.3 x 10(5) M-1 min-1, 6.9 x 10(4) M-1 min-1 and 1.1 x 10(4) M-1 min-1 for dichlorvos, sarin and soman, respectively. The corresponding values for plasma CarbE could not be calculated because of dominant spontaneous reactivation of inhibited CarbE. CarbE inhibited with these OPC in vitro spontaneously reactivate with half-times of 18, 143 and 497 min for sarin, dichlorvos and soman in plasma and 111, 163 and 297 min for sarin, soman and dichlorvos in liver, respectively. These results were also confirmed in experiments in vivo in which rats were subcutaneously treated with 0.5 LD50 of these agents. The half-times of spontaneous reactivation of rat plasma CarbE in vivo were 1.2, 2.0 and 2.7 h for dichlorvos, sarin and soman, respectively. These findings have changed current understanding of the mechanism of interaction of CarbE with OPC and involvement of the enzymes in detoxication of OPC, suggesting an active and important role of the enzymes in metabolic conversions of OPC to their less toxic metabolites.

show abstract

The mechanism of soman detoxification in perfused rat liver

Cited by 18 publications

References 14 publications

Detoxification of soman in the perfused rat liver: Quantitative uptake and stereoisomer metabolism

Detoxification of soman in the perfused rat liver: Quantitative uptake and stereoisomer metabolism

Development of Tolerance to the Toxicity of Xenobiotics

Interaction of organophosphorus compounds with carboxylesterases in the rat

Contact Info

Product

Resources

About