title: Stereospecific hydrolysis of a phosphoramidate used as an OPIDP model by human sera with PON1 192 alloforms.
abstract: O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) is a racemic organophosphate compound (OP) that induces delayed neuropathy in vivo. The O-hexyl 2,5-dichlorophenyl phosphoramidate R (R-HDCP) isomer inhibits and ages neuropathic target esterase (NTE) in hen brain. Moreover, human serum paraoxonase-1 (PON1) is a Ca(2+)-dependent enzyme capable of hydrolyzing OPs. The enzymatic activity of PON1 against OPs depends on the genetic polymorphisms present at position 192 (glutamine or arginine). The catalytic efficiency of PON1 is an important factor that determines neurotoxic susceptibility to some OPs. In the present study, we characterized the stereospecific hydrolysis of HDCP by alloforms PON1 Q192R human serum by chiral chromatography. Forty-seven human samples were characterized for the PON1 192 polymorphism. The hydrolysis data demonstrate that the three alloforms of PON1 show an exclusive and significant stereospecific Ca(2+)-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate S isomer (S-HDCP) at 19-127 µM at the concentrations that remain in all the samples. This stereoselective Ca(2+)-dependent hydrolysis of S-HDCP is inhibited by EDTA and is independent of the PON1 Q192R alloform. The present research reinforces the hypothesis that R-HDCP (an isomer that inhibits and causes NTE aging) is the enantiomer that induces delayed neuropathy by this chiral phosphoramidate due to the low hydrolysis level of the R-HDCP observed in this study.
authors.affiliation: Laboratorio de Neuroprotección, Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, 62209, Cuernavaca, Morelos, Mexico. amonroy@uaem.mx.
authors.forename: Antonio
authors.initials: A
authors.lastname: Monroy-Noyola
authors.affiliation: Laboratorio de Neuroprotección, Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, 62209, Cuernavaca, Morelos, Mexico.
authors.forename: Bertín
authors.initials: B
authors.lastname: Trujillo
authors.affiliation: Departamento de Neurogenética, Instituto Nacional de Neurología y Neurocirugía, M.V.S., Mexico, DF, Mexico.
authors.forename: Petra
authors.initials: P
authors.lastname: Yescas
authors.affiliation: Laboratorio de Neuroprotección, Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, 62209, Cuernavaca, Morelos, Mexico.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Martínez-Salazar
authors.affiliation: Laboratorio de Neuroprotección, Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col. Chamilpa, 62209, Cuernavaca, Morelos, Mexico.
authors.forename: Sara
authors.initials: S
authors.lastname: García-Jiménez
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, M.V.S., Mexico, DF, Mexico.
authors.forename: Camilo
authors.initials: C
authors.lastname: Ríos
authors.affiliation: Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Alicante, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Vilanova
mesh_terms: D000328:Adult; D043303:Aryldialkylphosphatase / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000633:toxicity*; D011110:Polymorphism, Genetic; D011115:Polyneuropathies / Q000139:chemically induced*; D013237:Stereoisomerism
chemical_list: D009943:Organophosphorus Compounds; C066606:hexyl 2,5-dichlorophenylphosphoroamidate; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D002118:Calcium
keywords: Chiral; Human serum; Hydrolysis; Organophosphorus; Paraoxonase-1; Stereospecificity