Structure-activity relationships in the deacetylation of O-glucosides of N-hydroxy-N-arylacylamides by mammalian liver microsomes.
Structure-activity relationships in the deacylation of O-glucosides of N-hydroxy-N-aryl-acylamides were investigated to provide insights into the metabolic activation of carcinogenic/mutagenic O-glycosides of N-hydroxy-N-arylacylamides. In the subcellular fractions obtained from porcine liver, the deacetylation activity toward O-glucoside of N-hydroxyacetanilide (GAc) was mainly localized in the microsomes. Both the 2-chloro (2ClGAc) 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 AM1 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 differences in the microsomal deacetylation activity toward GAc, and the highest activity was found in the rabbit, followed by the porcine, hamster, rat and then bovine liver microsomes.
Yoshioka
T
T
Department of Chemical Hygiene, Hokkaido Institute of Pharmaceutical Sciences, Otaru 047-0264, Japan.
Tatsunami
R
R
Ohno
H
H
Uematsu
T
T
D000814:Aniline Compounds / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002458:Cell Fractionation; D005960:Glucosides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D000814:Aniline Compounds; D005960:Glucosides; C439297:N-acetylanilino glucopyranoside