Species differences in tissue distribution and enzyme activities of arylacetamide deacetylase in human, rat, and mouse.
Human arylacetamide deacetylase (AADAC) is a major esterase responsible for the hydrolysis of clinical drugs such as flutamide, phenacetin, and rifampicin. Thus, AADAC is considered to be a relevant enzyme in preclinical drug development, but there is little information about species differences with AADAC. This study investigated the species differences in the tissue distribution and enzyme activities of AADAC. In human, AADAC mRNA was highly expressed in liver and the gastrointestinal tract, followed by bladder. In rat and mouse, AADAC mRNA was expressed in liver at the highest level, followed by the gastrointestinal tract and kidney. The expression levels in rat tissues were approximately 7- and 10-fold lower than those in human and mouse tissues, respectively. To compare the catalytic efficiency of AADAC among three species, each recombinant AADAC was constructed, and enzyme activities were evaluated by normalizing with the expression levels of AADAC. Flutamide and phenacetin hydrolase activities were detected by the recombinant AADAC of all species. In flutamide hydrolysis, liver microsomes of all species showed similar catalytic efficiencies, despite the lower AADAC mRNA expression in rat liver. In phenacetin hydrolysis, rat liver microsomes showed approximately 4- to 6.5-fold lower activity than human and mouse liver microsomes. High rifampicin hydrolase activity was detected only by recombinant human AADAC and human liver and jejunum microsomes. Taken together, the results of this study clarified the species differences in the tissue distribution and enzyme activities of AADAC and facilitate our understanding of species differences in drug hydrolysis.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Yuki
Y
Kobayashi
Tatsuki
T
Fukami
Akinori
A
Nakajima
Akinobu
A
Watanabe
Miki
M
Nakajima
Tsuyoshi
T
Yokoi
D000595:Amino Acid Sequence; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D055808:Drug Discovery; D005260:Female; D005485:Flutamide / Q000493:pharmacokinetics; D041981:Gastrointestinal Tract / Q000201:enzymology; D006868:Hydrolysis; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010615:Phenacetin / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D012293:Rifampin / Q000493:pharmacokinetics; D016415:Sequence Alignment; D013045:Species Specificity; D013379:Substrate Specificity; D014018:Tissue Distribution
D012333:RNA, Messenger; D005485:Flutamide; C569302:AADAC protein, human; C439668:Aadac protein, mouse; D002265:Carboxylic Ester Hydrolases; C574026:arylacetamide deacetylase, rat; D010615:Phenacetin; D012293:Rifampin