title: A novel polymorphic allele of human arylacetamide deacetylase leads to decreased enzyme activity.
abstract: Human arylacetamide deacetylase (AADAC) is responsible for the hydrolysis of clinically used drugs such as flutamide, phenacetin, and rifamycins. Our recent studies suggested that human AADAC is a relevant enzyme pharmacologically and toxicologically. To date, the genetic polymorphisms that affect enzyme activity in AADAC have been unknown. In this study, we found single-nucleotide polymorphisms in the human AADAC gene in a liver sample that showed remarkably low flutamide hydrolase activity. Among them, g.13651G > A (V281I) and g.14008T > C (X400Q) were nonsynonymous. The latter would be predicted to cause a C-terminal one-amino acid (glutamine) extension. The AADAC*2 allele (g.13651G > A) was found in all populations investigated in this study (European American, African American, Korean, and Japanese), at allelic frequencies of 52.6 to 63.5%, whereas the AADAC*3 allele (g.13651G > A/g.14008T > C) was found in European American (1.3%) and African American (2.0%) samples. COS7 cells expressing AADAC.1 (wild-type) exhibited flutamide, phenacetin, and rifampicin hydrolase activities with intrinsic clearance (CLint) values of 1.31 ± 0.06, 1.00 ± 0.02, and 0.39 ± 0.02 μl x min(-1) x unit(-1), respectively. AADAC.2, which is a protein produced from the AADAC*2 allele, showed moderately lower or similar CLint values, compared with AADAC.1, but AADAC.3 showed substantially lower CLint values (flutamide hydrolase, 0.21 ± 0.02 μl x min(-1) x unit(-1); phenacetin hydrolase, 0.12 ± 0.00 μl x min(-1) x unit(-1); rifampicin hydrolase, 0.03 ± 0.01 μl x min(-1) x unit(-1), respectively). Microsomes from a liver sample genotyped as AADAC*3/AADAC*3 showed decreased enzyme activities, compared with those genotyped as AADAC*1/AADAC*1, AADAC*1/AADAC*2, and AADAC*2/AADAC*2. In conclusion, we found an AADAC allele that yielded decreased enzyme activity. This study should provide useful information on interindividual variations in AADAC enzyme activity.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Shimizu
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Masataka
authors.initials: M
authors.lastname: Takamiya
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Aoki
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000483:Alleles; D000818:Animals; D019556:COS Cells; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: C569302:AADAC protein, human; D002265:Carboxylic Ester Hydrolases