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Enantioselective hydrolysis of oxazepam 3‐acetate by esterases in human and rat liver microsomes and rat brain s9 fraction
Author(s) -
Yang Shen K.,
Liu Kan,
Guengerich F. Peter
Publication year - 1990
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530020305
Subject(s) - chemistry , microsome , oxazepam , enantioselective synthesis , hydrolysis , fraction (chemistry) , chromatography , biochemistry , organic chemistry , enzyme , catalysis , receptor , benzodiazepine
Rates of hydrolysis of racemic and enantiomeric oxazepam 3‐acetates (OXA) by esterases in human and rat liver microsomes and rat brain S9 fraction were compared. When rac‐OXA was the substrate, esterases in human and rat liver microsomes were highly enantioselective toward (R)‐OXA. In contrast, esterases in rat brain S9 fraction were highly enantioselective toward (S)‐OXA. Hydrolysis rates of rac‐OXA were highly dependent on the amount of esterases used. At 0.05 mg protein equivalent of esterases and 150 nmol of rac‐OXA per ml of incubation mixture, the (R)‐OXA was hydrolyzed 3.6‐fold and 18.5‐fold faster than (S)‐OXA by rat and human liver microsomes, respectively. The specific activities (nmol of OXA hydrolyzed/mg microsomal protein/min) of liver microsomes in the hydrolysis of enantiomerically pure (R)‐OXA were approximately 120 (rat) and 1,980 (human), and in the hydrolysis of enantiomerically pure (S)‐OXA were 4 (rat) and 7 (human), respectively. In the incubation of rac‐OXA with rat brain S9 fraction, (S)‐OXA was hydrolyzed ∼6‐fold faster than (R)‐OXA. Results also indicated an enantiomeric interaction in the hydrolysis of rac‐OXA by esterases in rat and human liver microsomes; the presence of (R)‐OXA stimulated the hydrolysis of (S)‐OXA, whereas the presence of (S)‐OXA inhibited the hydrolysis of (R)‐OXA. In rat brain S9 fraction, the presence of (R)‐OXA inhibited the hydrolysis of (S)‐OXA, whereas the presence of (S)‐OXA appeared to have stimulated the hydrolysis of (R)‐OXA.