Shimizu_2012_Drug.Metab.Dispos_40_1183

Reference

Title : A novel polymorphic allele of human arylacetamide deacetylase leads to decreased enzyme activity - Shimizu_2012_Drug.Metab.Dispos_40_1183
Author(s) : Shimizu M , Fukami T , Kobayashi Y , Takamiya M , Aoki Y , Nakajima M , Yokoi T
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 40 :1183 , 2012
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 mul 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 mul x min(-1) x unit(-1); phenacetin hydrolase, 0.12 +/- 0.00 mul x min(-1) x unit(-1); rifampicin hydrolase, 0.03 +/- 0.01 mul 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.

PubMedSearch : Shimizu_2012_Drug.Metab.Dispos_40_1183
PubMedID: 22415931
Gene_locus related to this paper: human-AADAC

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Citations formats

Shimizu M, Fukami T, Kobayashi Y, Takamiya M, Aoki Y, Nakajima M, Yokoi T (2012)
A novel polymorphic allele of human arylacetamide deacetylase leads to decreased enzyme activity
Drug Metabolism & Disposition: The Biological Fate of Chemicals 40 :1183

Shimizu M, Fukami T, Kobayashi Y, Takamiya M, Aoki Y, Nakajima M, Yokoi T (2012)
Drug Metabolism & Disposition: The Biological Fate of Chemicals 40 :1183