Stereospecific hydrolysis of a phosphoramidate as a model to understand the role of biotransformation in the neurotoxicity of chiral organophosphorus compounds.
Calcium-dependent and EDTA-resistant hydrolyses of R and S isomers of O-hexyl O-2,5-dicholorophenyl phosphoramidate (HDCP) were observed in serum and subcellular fractions of liver, kidney and brain from hen, rat and rabbit. In serum, the Ca(2+)-dependent hydrolysis was much higher in rabbit than in other species. Liver showed a higher activity than kidney and brain. The S-HDCP isomer was hydrolysed to a higher extent than the other isomer. The fact that this stereospecificity favours the S-isomer is more clearly observed in rabbit serum, and in rat and rabbit liver particulate fractions. In such tissues and species, the EDTA-resistant hydrolysis was not stereospecific. Soluble fractions of rat brain and of hen liver, kidney and brain, showed a lower total activity but with a higher proportion of EDTA-resistant activity and a higher hydrolysis of the R-HDCP isomer. The Ca(2+)-dependent stereoselective biodegradation of S-HDCP is dominant in the most active tissues in rabbit and rat. It can therefore be concluded that S-HDCP would be biodegraded faster than R-HDCP. Furthermore, R-HDCP is the isomer that will remain at a higher proportion to be available for interaction with the target of neurotoxicity.
Monroy-Noyola
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Laboratorio de Neuroprotección, Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Universidad 1001, Chamilpa, C.P. 62210 Cuernavaca, México.
Sogorb
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MA
Vilanova
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E
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D002645:Chickens; D005260:Female; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions; D013379:Substrate Specificity
D009943:Organophosphorus Compounds; C066606:hexyl 2,5-dichlorophenylphosphoroamidate