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Titolo:
Structure-activity relationships in the deacetylation of O-glucosides of N-hydroxy-N-arylacylamides by mammalian liver microsomes
Autore:
Yoshioka, T; Tatsunami, R; Ohno, H; Uematsu, T;
Indirizzi:
Hokkaido Inst Pharmaceut Sci, Dept Chem Hyg, Otaru, Hokkaido 0470264, Japan Hokkaido Inst Pharmaceut Sci Otaru Hokkaido Japan 0470264 0470264, Japan
Titolo Testata:
CHEMICO-BIOLOGICAL INTERACTIONS
fascicolo: 1, volume: 137, anno: 2001,
pagine: 25 - 42
SICI:
0009-2797(20010731)137:1<25:SRITDO>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
NITROSO AROMATIC-COMPOUNDS; RETINYL ESTER HYDROLASE; SPECIES-DIFFERENCES; RAT; PURIFICATION; ACIDS; CARBOXYLESTERASES; 4-NITROBIPHENYL; ARYLACETAMIDES; ACTIVATION;
Keywords:
O-glucosides of N-hydroxy-N-arylacylamides; carboxylesterase; deacetylation species difference; HOMO; LUMO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Uematsu, T Hokkaido Inst Pharmaceut Sci, Dept Chem Hyg, Otaru, Hokkaido 0470264, Japan Hokkaido Inst Pharmaceut Sci Otaru Hokkaido Japan 0470264 apan
Citazione:
T. Yoshioka et al., "Structure-activity relationships in the deacetylation of O-glucosides of N-hydroxy-N-arylacylamides by mammalian liver microsomes", CHEM-BIO IN, 137(1), 2001, pp. 25-42

Abstract

Structure-activity relationships in the deacylation of O-glucosides of N-hydroxy-N-arylacylamides were investigated to provide insights into the metabolic activation of carcino-genic/mutagenic. O-glycosides of N-hydroxy-N-arylacylamides. In the subcellular fractions obtained from porcine liver, thedeacetylation activity toward O-glucoside of N-hydroxyacetanilide (GAc) was mainly localized in the microsomes. Both the 2-chloro (2CIGAc) and 2-methyl (2MeGAc) derivatives of GAc were not deacetylated by the microsomes. Other compounds having either 3- or 4-substituent (chloro or methyl), however,were deacetylated and showed higher V-max/K-m values than that of GAc. 4-Methyl derivative (4MeGAc) was shown to competitively inhibit the deacetylation activity toward GAc, and the K-i value of 4MeGAc was comparable with its K-m value obtained in the microsome-catalyzed deacetylation. These apparent K-m values were shown to correspond to their lipophilicities estimated from retention times on high-performance liquid chromatography (HPLC), As for the effect of acyl groups, the order of V-max/K-m values was N-propionyl derivative (GPr) > GAc > N-butyryl derivative (GBu). From the optimized structures and energy levels of the frontier orbitals of these compounds, calculated by the semi-empirical AMI method, the effects of 2-substituents and acyl groups on the deacetylation activity is thought to be due to a steric factor. From the energy levels of the frontier orbitals of GAc and its 3- or 4-substituted derivatives, the compound having a lower level of LUMO was shown to be deacetylated effectively. There were marked species differencesin the microsomal deacetylation activity toward GAc, and the highest activity was found in the rabbit, followed by the porcine, hamster, rat and thenbovine liver microsomes. (C) 2001 Elsevier Science Ireland Ltd, All rightsreserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 23:36:10