Catalog of 680 variations among eight cytochrome P450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population

Saito, Susumu; Iida, Aritoshi; Sekine, Akihiro; Kawauchi, Saori; Higuchi, Sadaharu; Ogawa, Chie; Nakamura, Yusuke

doi:10.1007/s10038-003-0021-7

Cited by 29 publications

(14 citation statements)

References 73 publications

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“…In this report, a 33% overestimation of the frequency of CYP2A6 Ã 4A&D due to CYP2A6 Ã 28A was found. This may be of particular importance in Asian populations because the frequency of CYP2A6 Ã 4 is much higher , the frequency of CYP2A6 Ã 28A is unknown, and the 5750G4C sequence variant (found in CYP2A6 Ã 28A) was first identified in a Japanese population [Saito et al, 2003].…”

Section: Discussionmentioning

confidence: 99%

“…Our primary aim was to characterize four CYP2A6 nonsynonymous sequence variants, namely 594G4C (p.V110L) [Haberl et al, 2005], 1672T4C (p.F118L) [Solus et al, 2004], 2162_2163GC4A (R203frameshift [FS]) [Solus et al, 2004], and 5750G4C (p.E419D) [Saito et al, 2003], with respect to their haplotype, allele frequency, and in vivo functional impact. A secondary aim was to confirm whether established CYP2A6 alleles that have been predominately discovered and characterized in Caucasian and Asian populations have similar pharmacokinetic effects in a population of Black African descent.…”

Section: Introductionmentioning

confidence: 99%

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Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent

et al. 2008

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Cytochrome P450 2A6 (CYP2A6) is a human enzyme best known for metabolizing tobacco-related compounds, such as nicotine, cotinine (COT), and nitrosamine procarcinogens. CYP2A6 genetic variants have been associated with smoking status, cigarette consumption, and tobacco-related cancers. Our objective was to functionally characterize four nonsynonymous CYP2A6 sequence variants with respect to their haplotype, allele frequency, and association with in vivo CYP2A6 activity. In vivo, nicotine was administered orally to 281 volunteers of Black African descent. Blood samples were collected for kinetic phenotyping and CYP2A6 genotyping. In vitro, nicotine C-oxidation catalytic efficiencies of heterologously expressed variant enzymes were assessed. The four uncharacterized sequence variants were found in seven novel alleles CYP2A6(*)24A&B ; (*)25, (*)26, (*)27, and *28A&B, most were associated with impaired in vivo CYP2A6 activity. Nicotine metabolism groupings, based on the in vivo data of variant alleles, were created. Mean trans-3'-hydroxycotinine/cotinine (3HC/COT) differed (P<0.001) between normal (100%), intermediate (64%), and slow (40%) groups. Systemic exposure to nicotine following oral administration also differed (P<0.001) between normal (100%), intermediate (139%), and slow (162%) metabolism groups. In addition, alleles of individuals with unusual phenotype-genotype relationships were sequenced, resulting in the discovery of five novel uncharacterized alleles and at least one novel duplication allele. A total of 7% of this population of Black African descent had at least one of the eight novel characterized alleles and 29% had at least one previously established allele. These findings are important for increasing the accuracy of association studies between CYP2A6 genotype and behavioral, disease, or pharmacological phenotypes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent

et al. 2008

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“…However, the regulation mechanisms of human AADAC expression are not fully understood. Saito et al (2003) previously found 23 SNPs in the AADAC gene using DNA samples of 48 Japanese. Among them, only an SNP that was also found in this study (g.13651G Ͼ A, c.931G Ͼ A) leads to an amino acid change (V281I).…”

Section: Discussionmentioning

confidence: 99%

Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis

Watanabe

Fukami²,

Nakajima³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The initial metabolic pathways of flutamide are hydroxylation and hydrolysis. It was recently reported that the hydrolyzed product, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. However, the esterase responsible for the flutamide hydrolysis has not been characterized. In the present study, we found that human arylacetamide deacetylase (AADAC) efficiently hydrolyzed flutamide using recombinant AADAC expressed in COS7 cells. In contrast, carboxylesterase1 (CES1) and CES2, which are responsible for the hydrolysis of many drugs, could not hydrolyze flutamide. AADAC is specifically expressed in the endoplasmic reticulum. Flutamide hydrolase activity was highly detected in human liver microsomes (K m , 794 ؎ 83 M; V max , 1.1 ؎ 0.0 nmol/min/mg protein), whereas the activity was extremely low in human liver cytosol. The flutamide hydrolase activity in human liver microsomes was strongly inhibited by bis-(nonylphenyl)-phenylphosphate, diisopropylphosphorofluoride, and physostigmine sulfate (eserine) but moderately inhibited by sodium fluoride, phenylmethylsulfonyl fluoride, and disulfiram. The same inhibition pattern was obtained with the recombinant AADAC. Moreover, human liver and jejunum microsomes showing AADAC expression could hydrolyze flutamide, but human pulmonary and renal microsomes, which do not express AADAC, showed slight activity. In human liver microsomal samples (n ‫؍‬ 50), the flutamide hydrolase activities were significantly correlated with the expression levels of AADAC protein (r ‫؍‬ 0.66, p < 0.001). In conclusion, these results clearly showed that flutamide is exclusively hydrolyzed by AADAC. AADAC would be an important enzyme responsible for flutamideinduced hepatotoxicity.Flutamide (3Ј-trifluoro-2-methyl-4Ј-nitro-2-methyl-propinoylanilide) is a nonsteroidal antiandrogen drug used for the treatment of prostate cancer. The combination of luteinizing hormone-releasing hormone agonist results in prolonged survival in prostate cancer patients (Crawford et al., 1989). However, flutamide occasionally causes severe hepatotoxicity (Thole et al., 2004). Flutamide itself is not toxic when used at the appropriate clinical dose, but bioactivation of flutamide has been considered to be the cause of flutamide-induced hepatotoxicity (Fau et al., 1994).Flutamide is mainly metabolized to 2-hydroxyflutamide by human CYP1A2. It has been suggested that 2-hydroxyflutamide is associated with the therapeutic effect of flutamide (Katchen and Buxbaum, 1975). Flutamide is also hydrolyzed to 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) by esterase (Katchen and Buxbaum, 1975;Schulz et al., 1988). FLU-1 is considered to have no therapeutic effect (Aizawa et al., 2003). Goda et al. (2006) recently reported that FLU-1 is further metabolized to N-hydroxyl FLU-1 by human CYP3A4. Many researchers have reported on the relationship between the toxicity and metabolism...

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“…Because of the large resemblance between the CES1A1 and CES1A2 promoter sequences, the SNPs on this region (29) are hardly distinguishable. We reported that several SNPs exist exclusively on the promoter regions of CES1A1 or CES1A2, respectively (Yoshimura et al, under submission).…”

Section: Discussionmentioning

confidence: 99%

A Single Nucleotide Polymorphism in the Carboxylesterase Gene Is Associated with the Responsiveness to Imidapril Medication and the Promoter Activity

et al. 2005

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Catalog of 680 variations among eight cytochrome P450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population

Cited by 29 publications

References 73 publications

Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent

Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent

Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis

A Single Nucleotide Polymorphism in the Carboxylesterase Gene Is Associated with the Responsiveness to Imidapril Medication and the Promoter Activity

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