Contributions of Arylacetamide Deacetylase and Carboxylesterase 2 to Flutamide Hydrolysis in Human Liver

Kobayashi, Yuki; Fukami, Tatsuki; Shimizu, Mai; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1124/dmd.112.044537

Cited by 41 publications

(34 citation statements)

References 21 publications

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“…PNPA is a known marker of CES activity (Hosokawa et al, 1995). Flutamide is also hydrolyzed by CES2 (Kobayashi et al, 2012b). These findings revealed that substrate specificity of AADAC appears to partly overlap with those of CES enzymes.…”

Section: Resultsmentioning

confidence: 56%

Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

et al. 2014

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Esterases catalyze the hydrolysis of therapeutic drugs containing esters or amides in their structures. Human carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes that catalyze the hydrolysis of drugs in the liver. Characterization of the enzyme(s) responsible for drug metabolism is required in drug development and to realize optimal drug therapy. Because multiple enzymes may show a metabolic potency for a given compound, inhibition studies using chemical inhibitors are useful tools to determine the contribution of each enzyme in human tissue preparations. The purpose of this study was to find specific inhibitors for human CES1, CES2, and AADAC. We screened 542 chemicals for the inhibition potency toward hydrolase activities of p-nitrophenyl acetate by recombinant CES1, CES2, and AADAC. We found that digitonin and telmisartan specifically inhibited CES1 and CES2 enzyme activity, respectively. Vinblastine potently inhibited both AADAC and CES2, but no specific inhibitor of AADAC was found. The inhibitory potency and specificity of these compounds were also evaluated by monitoring the effects on hydrolase activity of probe compounds of each enzyme (CES1: lidocaine, CES2: CPT-11, AADAC: phenacetin) in human liver microsomes. Telmisartan and vinblastine strongly inhibited the hydrolysis of CPT-11 and/or phenacetin, but digitonin did not strongly inhibit the hydrolysis of lidocaine, indicating that the inhibitory potency of digitonin was different between recombinant CES1 and liver microsomes. Although we could not find a specific inhibitor of AADAC, the combined use of telmisartan and vinblastine could predict the responsibility of human AADAC to drug hydrolysis.

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Section: Resultsmentioning

confidence: 56%

Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

et al. 2014

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“…Phenacetin and rifampicin are specific substrates for human AADAC (Watanabe et al, 2010;Nakajima et al, 2011). Although CES2 also contributes to flutamide hydrolysis, we previously found that its activity at 500 mM reflects the AADAC enzyme activity (Kobayashi et al, 2012b). PNPA is hydrolyzed by multiple esterases, including the CES enzymes (Watanabe et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…PNPA is hydrolyzed by multiple esterases, including the CES enzymes (Watanabe et al, 2009). Fenofibrate and irinotecan are selected as marker probes for CES1 and CES2, respectively Kobayashi et al, 2012b). The indiplon hydrolase activity was significantly correlated (P , 0.001) to the phenacetin (r = 0.84), rifampicin (r = 0.86), and flutamide hydrolase activities (r = 0.87).…”

Section: Resultsmentioning

confidence: 99%

Indiplon Is Hydrolyzed by Arylacetamide Deacetylase in Human Liver

Shimizu¹,

Fukami²,

Ito³

et al. 2014

Drug Metab Dispos

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Human arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of some clinically used drugs, but the information available on its substrates is limited. To increase our knowledge of the AADAC substrates, we examined whether AADAC catalyzes the hydrolysis of indiplon, which was initially developed as a hypnotic sedative drug. It has been reported that approximately 30-40% of the administered indiplon was hydrolyzed to deacetylindiplon in humans, but the enzyme responsible for this hydrolysis had not been identified. We detected high levels of indiplon hydrolase activity in human liver microsomes (HLMs), but the levels found in human liver cytosol and plasma were scarcely detectable. Recombinant AADAC showed a high level of indiplon hydrolase activity, whereas recombinant carboxylesterase 1 (CES1) and 2 (CES2) showed marginal activity. The indiplon hydrolase activity of HLM was potently inhibited by vinblastine, a potent inhibitor of AADAC and CES2, but it was not inhibited by digitonin and telmisartan, inhibitors of CES1 and CES2, respectively. In a panel of 24 individual HLM samples, the indiplon hydrolase activities were significantly correlated with the hydrolase activities of flutamide, phenacetin, and rifampicin, which are known AADAC substrates. An HLM sample with a homozygous AADAC*3 allele, which was previously found to exhibit decreased enzyme activity, showed the lowest indiplon hydrolase activity among the 24 tested samples. Collectively, we found that human AADAC is responsible for the hydrolysis of indiplon. Thus, we can add indiplon to the list of human AADAC substrates.

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“…Our recent study found that AADAC and carboxylesterase 2 are involved in the hydrolysis of flutamide in human liver at high and low concentrations, respectively (Kobayashi et al, 2012). When the flutamide hydrolase activity was analyzed with six individual human liver samples in that study, we found a human liver sample that showed extremely low flutamide hydrolase activity at a high concentration of 200 M but moderate activity at a low concentration of 5 M. This result indicated that the human liver sample showed extremely low AADAC enzyme activity.…”

Section: Introductionmentioning

confidence: 95%

A Novel Polymorphic Allele of Human Arylacetamide Deacetylase Leads to Decreased Enzyme Activity

Shimizu

Fukami²,

Kobayashi³

et al. 2012

Drug Metab Dispos

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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 express- , 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.

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Contributions of Arylacetamide Deacetylase and Carboxylesterase 2 to Flutamide Hydrolysis in Human Liver

Cited by 41 publications

References 21 publications

Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

Indiplon Is Hydrolyzed by Arylacetamide Deacetylase in Human Liver

A Novel Polymorphic Allele of Human Arylacetamide Deacetylase Leads to Decreased Enzyme Activity

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