Kurokawa T

References (9)

Title : Difference in substrate specificity of carboxylesterase and arylacetamide deacetylase between dogs and humans - Yoshida_2018_Eur.J.Pharm.Sci_111_167
Author(s) : Yoshida T , Fukami T , Kurokawa T , Gotoh S , Oda A , Nakajima M
Ref : Eur J Pharm Sci , 111 :167 , 2018
Abstract : Carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes responsible for the hydrolysis of various clinical drugs. Our recent study demonstrated that the identity of the responsible hydrolase can be roughly surmised based on the chemical structures of compounds in humans. Dogs are used for preclinical studies in drug development, but the substrate specificities of dog CES and AADAC remain to be clarified. The purpose of this study is to characterize their substrate specificities. We prepared recombinant dog CES1, CES2, and AADAC. p-Nitrophenyl acetate, a general substrate for esterases, was hydrolyzed by dog CES1 and AADAC, while it was not hydrolyzed by CES2. CES2 protein was not substantially detected in the recombinant system or in the dog liver and intestinal microsomes by Western blot using anti-human CES2 antibodies. In silico analyses demonstrated slight differences in the three-dimensional structures of dog CES2 and human CES2, indicating that dog CES2 might be unstable or inactive. By evaluating the hydrolase activities of 22 compounds, which are known to be substrates of human CES and/or AADAC, we found that the activities of dog recombinant CES1 and AADAC as well as dog tissue preparations for nearly all compounds were lower than those of human enzymes. The dog enzymes that were responsible for the hydrolysis of most compounds corresponded to the human enzymes, but the following differences were observed: oseltamivir, irinotecan, and rifampicin were not hydrolyzed in the dog liver or by any of the recombinant esterases and procaine, a human CES2 substrate, was hydrolyzed by dog CES1. In conclusion, the present study could provide new finding to facilitate our understanding of species differences in drug hydrolysis, which can facilitate drug development and drug safety evaluation.
ESTHER : Yoshida_2018_Eur.J.Pharm.Sci_111_167
PubMedSearch : Yoshida_2018_Eur.J.Pharm.Sci_111_167
PubMedID: 28966098
Gene_locus related to this paper: canfa-CESDD1 , canfa-f1p6w8 , canlf-e2r2h2

Title : Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog - Kurokawa_2016_Drug.Metab.Dispos_44_409
Author(s) : Kurokawa T , Fukami T , Yoshida T , Nakajima M
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 44 :409 , 2016
Abstract : Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CLint value of 50.0 +/- 1.2 ml/min/mg protein with a similar Km value to human intestinal and liver microsomes, whereas the CLint values of human CES1 and CES2 were 4.6 +/- 0.1 and 6.6 +/- 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar Km values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.
ESTHER : Kurokawa_2016_Drug.Metab.Dispos_44_409
PubMedSearch : Kurokawa_2016_Drug.Metab.Dispos_44_409
PubMedID: 26718653

Title : Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases - Fukami_2015_Eur.J.Pharm.Sci_78_47
Author(s) : Fukami T , Kariya M , Kurokawa T , Iida A , Nakajima M
Ref : Eur J Pharm Sci , 78 :47 , 2015
Abstract : Human arylacetamide deacetylase (AADAC) is an esterase responsible for the hydrolysis of some drugs, including flutamide, indiplon, phenacetin, and rifamycins. AADAC is highly expressed in the human liver, where carboxylesterase (CES) enzymes, namely, CES1 and CES2, are also expressed. It is generally recognized that CES1 prefers compounds with a large acyl moiety and a small alcohol or amine moiety as substrates, whereas CES2 prefers compounds with a small acyl moiety and a large alcohol or amine moiety. In a comparison of the chemical structures of known AADAC substrates, AADAC most likely prefers compounds with the same characteristics as does CES2. However, the substrate specificity of human AADAC has not been fully clarified. To expand the knowledge of substrates of human AADAC, we measured its hydrolase activities toward 13 compounds, including known human CES1 and CES2 substrates, using recombinant enzymes expressed in Sf21 cells. Recombinant AADAC catalyzed the hydrolysis of fluorescein diacetate, N-monoacetyldapsone, and propanil, which possess notably small acyl moieties, and these substrates were also hydrolyzed by CES2. However, AADAC could not hydrolyze another CES2 substrate, procaine, which possesses a moderately small acyl moiety. In addition, AADAC did not hydrolyze several known CES1 substrates, including clopidogrel and oseltamivir, which have large acyl moieties and small alcohol moieties. Collectively, these results suggest that AADAC prefers compounds with smaller acyl moieties than does CES2. The role of AADAC in the hydrolysis of drugs has been clarified. For this reason, AADAC should receive attention in ADMET studies during drug development.
ESTHER : Fukami_2015_Eur.J.Pharm.Sci_78_47
PubMedSearch : Fukami_2015_Eur.J.Pharm.Sci_78_47
PubMedID: 26164127
Gene_locus related to this paper: human-AADAC , human-CES1 , human-CES2

Title : Characterization of Species Differences in Tissue Diltiazem Deacetylation Identifies Ces2a as a Rat-Specific Diltiazem Deacetylase - Kurokawa_2015_Drug.Metab.Dispos_43_1218
Author(s) : Kurokawa T , Fukami T , Nakajima M
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 43 :1218 , 2015
Abstract : Diltiazem, a calcium channel blocker, is mainly metabolized via demethylation or deacetylation in humans. Diltiazem demethylation is catalyzed by cytochrome P450 2D6 and 3A4. Although it was previously reported that the area under the curve ratio of deacetyldiltiazem to diltiazem after oral dosing with diltiazem in rats was sevenfold higher than in humans, the molecular mechanisms underlying this species difference remain to be clarified. In the present study, we compared the diltiazem deacetylase activity in liver, intestinal, renal, and pulmonary microsome preparations of human and experimental animal tissues to identify the specific deacetylase enzyme(s) involved in deacetylation. Diltiazem deacetylase activity was detected in rat liver and small intestine microsome preparations, but not in those from human, monkey, dog, and mouse tissues. Further purification of rat liver microsome (RLM) proteins identified four carboxylesterase (Ces) enzymes (Ces1d, Ces1e, Ces1f, and Ces2a) as potential candidate deacetylases. On the basis of their tissue distribution, the Ces2a enzyme was considered to be the enzyme that was responsible for diltiazem deacetylation. Furthermore, recombinant rat Ces2a expressed in Sf21 cells displayed efficient diltiazem deacetylase activity with similar Km values as RLM. In addition, the inhibitory characteristics of various chemical inhibitors were similar between recombinant rat Ces2a and RLM. In conclusion, we determined that only rat tissues were able to catalyze diltiazem deacetylation. The characterization of Ces enzymes in animal species, as undertaken in this study, will prove useful to predict the species-specific pharmacokinetics differences between the in vivo models used for drug development.
ESTHER : Kurokawa_2015_Drug.Metab.Dispos_43_1218
PubMedSearch : Kurokawa_2015_Drug.Metab.Dispos_43_1218
PubMedID: 25979260

Title : Indiplon is hydrolyzed by arylacetamide deacetylase in human liver - Shimizu_2014_Drug.Metab.Dispos_42_751
Author(s) : Shimizu M , Fukami T , Ito Y , Kurokawa T , Kariya M , Nakajima M , Yokoi T
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 42 :751 , 2014
Abstract : 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.
ESTHER : Shimizu_2014_Drug.Metab.Dispos_42_751
PubMedSearch : Shimizu_2014_Drug.Metab.Dispos_42_751
PubMedID: 24464802

Title : Lipoprotein lipase activator NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin-induced diabetic rats - Kusunoki_2004_Metabolism_53_260
Author(s) : Kusunoki M , Tsutsumi K , Inoue Y , Hara T , Miyata T , Nakamura T , Ogawa H , Sakakibara F , Fukuzawa Y , Okabayashi N , Kato K , Ikeda H , Kurokawa T , Ishikawa T , Otake K , Nakaya Y
Ref : Metabolism , 53 :260 , 2004
Abstract : NO-1886 is a lipoprotein lipase (LPL) activator. Administration of NO-1886 results in an increase in plasma high-density lipoprotein cholesterol (HDL-C) and a decrease in plasma triglyceride (TG) levels. The aim of this study was to ascertain whether NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin (STZ)-induced diabetic rats. Administration of NO-1886 resulted in increased plasma HDL-C levels and decreased TG levels without affecting total cholesterol and glucose levels in the diabetic rats. NO-1886 dose-dependently decreased liver TG contents and cholesterol contents, resulting in improvement of fatty liver. NO-1886 also reduced plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that accompany fatty liver. The liver cholesterol contents were inversely correlated with plasma HDL-C levels (r = -0.5862, P <.001) and were positively correlated with plasma TG levels (r = 0.4083, P <.003). The liver TG contents were inversely correlated with plasma HDL-C levels (r = -0.6195, P <.001) and were positively correlated with plasma TG levels (r = 0.5837, P <.001). There was no correlation between plasma cholesterol levels, and cholesterol and TG contents in liver. These results indicate that reducing plasma TG levels and elevating in HDL-C levels may result in improving fatty liver.
ESTHER : Kusunoki_2004_Metabolism_53_260
PubMedSearch : Kusunoki_2004_Metabolism_53_260
PubMedID: 14767881

Title : Expression of pancreatic enzyme genes during the early larval stage of Japanese eel, Anguilla japonica. -
Author(s) : Kurokawa T , Suzuki T , Ohta H , Kagawa H , Tanaka H , Unuma T
Ref : Fish Sci , 68 :736 , 2002
PubMedID:
Gene_locus related to this paper: angja-1plip

Title : Physical mapping of the linear plasmid pSLA2-L and localization of the eryAI and actI homologs - Kinashi_1998_Biosci.Biotechnol.Biochem_62_1892
Author(s) : Kinashi H , Fujii S , Hatani A , Kurokawa T , Shinkawa H
Ref : Biosci Biotechnol Biochem , 62 :1892 , 1998
Abstract : The 200-kb linear plasmid pSLA2-L was suggested to be involved in the production of lankamycin and lankacidin in Streptomyces rochei 7434AN4. In this study, we have constructed a physical map for 23 PstI fragments of pSLA2-L, the sum of which was 206 kb. Detailed restriction maps for both ends of pSLA2-L revealed the presence of terminal inverted repeats, the size of which was found to be 2.1 kb by cloning and sequencing of the end-points. Hybridization experiments using two polyketide biosynthetic genes, eryAI and actI, located their homologous regions on PstI fragments A and I, respectively.
ESTHER : Kinashi_1998_Biosci.Biotechnol.Biochem_62_1892
PubMedSearch : Kinashi_1998_Biosci.Biotechnol.Biochem_62_1892
PubMedID: 9836424
Gene_locus related to this paper: strro-LKMAIII , strro-ORF5 , strro-Q83WZ1 , strro-Q83X18 , strro-Q83X79 , strro-Q83X92

Title : Cyclophostin, acetylcholinesterase inhibitor from Streptomyces lavendulae -
Author(s) : Kurokawa T , Suzuki K , Hayaoka T , Nakagawa T , Izawa T , Kobayashi M , Harada N
Ref : J Antibiot (Tokyo) , 46 :1315 , 1993
PubMedID: 8407597