Kitamura S

References (17)

Title : PROTAC-Mediated Selective Degradation of Cytosolic Soluble Epoxide Hydrolase Enhances ER Stress Reduction - Wang_2023_ACS.Chem.Biol__
Author(s) : Wang Y , Morisseau C , Takamura A , Wan D , Li D , Sidoli S , Yang J , Wolan DW , Hammock BD , Kitamura S
Ref : ACS Chemical Biology , : , 2023
Abstract : Soluble epoxide hydrolase (sEH) is a bifunctional enzyme responsible for lipid metabolism and is a promising drug target. Here, we report the first-in-class PROTAC small-molecule degraders of sEH. Our optimized PROTAC selectively targets the degradation of cytosolic but not peroxisomal sEH, resulting in exquisite spatiotemporal control. Remarkably, our sEH PROTAC molecule has higher potency in cellular assays compared to the parent sEH inhibitor as measured by the significantly reduced ER stress. Interestingly, our mechanistic data indicate that our PROTAC directs the degradation of cytosolic sEH via the lysosome, not through the proteasome. The molecules presented here are useful chemical probes to study the biology of sEH with the potential for therapeutic development. Broadly, our results represent a proof of concept for the superior cellular potency of sEH degradation over sEH enzymatic inhibition, as well as subcellular compartment-selective modulation of a protein by PROTACs.
ESTHER : Wang_2023_ACS.Chem.Biol__
PubMedSearch : Wang_2023_ACS.Chem.Biol__
PubMedID: 36947831
Gene_locus related to this paper: human-EPHX2

Title : First-in-human in vivo undefined imaging and quantification of monoacylglycerol lipase in the brain: a PET study with (18)F-T-401 - Takahata_2022_Eur.J.Nucl.Med.Mol.Imaging__
Author(s) : Takahata K , Seki C , Kimura Y , Kubota M , Ichise M , Sano Y , Yamamoto Y , Tagai K , Shimada H , Kitamura S , Matsuoka K , Endo H , Shinotoh H , Kawamura K , Zhang MR , Takado Y , Higuchi M
Ref : Eur J Nucl Med Mol Imaging , : , 2022
Abstract : PURPOSE: Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand (18)F-T-401. METHODS: Seven healthy males underwent 120-min dynamic (18)F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with (18)F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test-retest reproducibility of (18)F-T-401-PET were also evaluated. RESULTS: (18)F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (V(T)) values by best identifiability. V(T) values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated V(T) values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. CONCLUSIONS: Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. (18)F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of V(T) values consistent with known regional MAGL expressions. PET with (18)F-T-401-PET is promising tool for measurement of central MAGL.
ESTHER : Takahata_2022_Eur.J.Nucl.Med.Mol.Imaging__
PubMedSearch : Takahata_2022_Eur.J.Nucl.Med.Mol.Imaging__
PubMedID: 35022846
Gene_locus related to this paper: human-MGLL

Title : Discovery of small-molecule enzyme activators by activity-based protein profiling - Kok_2020_Nat.Chem.Biol_16_997
Author(s) : Kok BP , Ghimire S , Kim W , Chatterjee S , Johns T , Kitamura S , Eberhardt J , Ogasawara D , Xu J , Sukiasyan A , Kim SM , Godio C , Bittencourt JM , Cameron M , Galmozzi A , Forli S , Wolan DW , Cravatt BF , Boger DL , Saez E
Ref : Nat Chemical Biology , 16 :997 , 2020
Abstract : Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.
ESTHER : Kok_2020_Nat.Chem.Biol_16_997
PubMedSearch : Kok_2020_Nat.Chem.Biol_16_997
PubMedID: 32514184
Gene_locus related to this paper: human-LYPLAL1

Title : Inhibitory effects of organophosphate esters on carboxylesterase activity of rat liver microsomes - Tsugoshi_2020_Chem.Biol.Interact__109148
Author(s) : Tsugoshi Y , Watanabe Y , Tanikawa Y , Inoue C , Sugihara K , Kojima H , Kitamura S
Ref : Chemico-Biological Interactions , :109148 , 2020
Abstract : We investigated the inhibitory effects of 13 organophosphate esters (OPEs) and hydrolytic metabolites on the carboxylesterase activity of rat liver microsomes in vitro in order to examine whether there might be a potential impact on human health, and to elucidate the structure activity relationship. Among the test compounds, 2-ethylhexyl diphenyl phosphate (EDPhP) was the most potent inhibitor of carboxylesterase activity, as measured in terms of 4-nitrophenol acetate hydrolase activity, followed by tri-m-cresyl phosphate (TmCP), cresyl diphenyl phosphate (CDPhP) and triphenyl phosphate (TPhP). The IC50 values were as follows: EDPhP (IC50: 0.03muM)>TmCP (0.4muM)>CDPhP (0.8muM)>TPhP (14muM)>tris(1,3-dichloro-2-propyl) phosphate (17muM)>tris(2-ethylhexyl) phosphate (77muM)>tri-n-propyl phosphate (84muM)>tris(2-chloroethyl) phosphate (104muM)>tris(2-butoxyethyl) phosphate (124muM)>tri-n-butyl phosphate (230muM). The IC50 value of EDPhP was three orders of magnitude lower than that of bis(4-nitrophenyl) phosphate, which is widely used as an inhibitor of carboxylesterase. Trimethyl phosphate, triethyl phosphate and tris(2-chloroisopropyl) phosphate slightly inhibited the carboxylesterase activity; their IC50 values were above 300muM. Lineweaver-Burk plots indicated that the inhibition by several OPEs was non-competitive. Diphenyl and monophenyl phosphates, which are metabolites of TPhP, showed weaker inhibitory effects than that of TPhP.
ESTHER : Tsugoshi_2020_Chem.Biol.Interact__109148
PubMedSearch : Tsugoshi_2020_Chem.Biol.Interact__109148
PubMedID: 32511959

Title : Comparative study of the effect of 17 parabens on PXR-, CAR- and PPARalpha-mediated transcriptional activation - Fujino_2019_Food.Chem.Toxicol_133_110792
Author(s) : Fujino C , Watanabe Y , Sanoh S , Hattori S , Nakajima H , Uramaru N , Kojima H , Yoshinari K , Ohta S , Kitamura S
Ref : Food & Chemical Toxicology , 133 :110792 , 2019
Abstract : Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor alpha (PPARalpha), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2-C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7-C12) parabens showed up to 2-fold activation of PPARalpha at 10muM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR and PPARalpha, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.
ESTHER : Fujino_2019_Food.Chem.Toxicol_133_110792
PubMedSearch : Fujino_2019_Food.Chem.Toxicol_133_110792
PubMedID: 31472229

Title : Differentiation Between Dementia With Lewy Bodies And Alzheimer's Disease Using Voxel-Based Morphometry Of Structural MRI: A Multicenter Study - Matsuda_2019_Neuropsychiatr.Dis.Treat_15_2715
Author(s) : Matsuda H , Yokoyama K , Sato N , Ito K , Nemoto K , Oba H , Hanyu H , Kanetaka H , Mizumura S , Kitamura S , Shinotoh H , Shimada H , Suhara T , Terada H , Nakatsuka T , Kawakatsu S , Hayashi H , Asada T , Ono T , Goto T , Shigemori K
Ref : Neuropsychiatr Dis Treat , 15 :2715 , 2019
Abstract : Background: The differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is particularly important because DLB patients respond better to cholinesterase inhibitors but sometimes exhibit sensitivity to neuroleptics, which may cause worsening of clinical status. Antemortem voxel-based morphometry (VBM) using structural MRI has previously revealed that patients with DLB have normal hippocampal volume, but atrophy in the dorsal mesopontine area. Objectives: The aim of this multicenter study was to determine whether VBM of the brain stem in addition to that of medial temporal lobe structures improves the differential diagnosis of AD and DLB. Methods: We retrospectively chose 624 patients who were clinically diagnosed with either DLB (239 patients) or AD (385 patients) from 10 institutes using different MR scanners with different magnetic field strengths. In all cases, VBM was performed on 3D T1-weighted images. The degree of local atrophy was calculated using Z-score by comparison with a database of normal volumes of interest (VOIs) in medial temporal lobe (MTL) and the dorsal brain stem (DBS). The discrimination of DLB and AD was evaluated using Z-score values in these two VOIs. MRI data from 414 patients were used as the training data set to determine the classification criteria, with the MRI data from the remaining 210 patients used as the test data set. Results: The DLB and AD patients did not differ with respect to mean age or Mini-Mental State Examination scores. Z-index scores showed that there was significantly more atrophy in MTL of AD patients, compared to DLB patients and in DBS of DLB patients, compared to AD patients. The discrimination accuracies of VBM were 63.3% in the test data set and 73.4% in the training data set. Conclusion: VBM of DBS in addition to that of MTL improves the differentiation of DLB and AD.
ESTHER : Matsuda_2019_Neuropsychiatr.Dis.Treat_15_2715
PubMedSearch : Matsuda_2019_Neuropsychiatr.Dis.Treat_15_2715
PubMedID: 31571887

Title : Comparative study of hydrolytic metabolism of dimethyl phthalate, dibutyl phthalate and di(2-ethylhexyl) phthalate by microsomes of various rat tissues - Ozaki_2017_Food.Chem.Toxicol_100_217
Author(s) : Ozaki H , Sugihara K , Watanabe Y , Moriguchi K , Uramaru N , Sone T , Ohta S , Kitamura S
Ref : Food & Chemical Toxicology , 100 :217 , 2017
Abstract : Phthalates are used in food packaging, and are transferred to foods as contaminants. In this study, we examined the hydrolytic metabolism of dimethyl phthalate (DMP), dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) by rat tissue microsomes. We found that carboxylesterase and lipase contribute differently to these activities. When DMP, DBP and DEHP were incubated with rat liver microsomes, DBP was most effectively hydrolyzed to the phthalate monoester, followed by DMP, and the activity toward DEHP was marginal. In contrast, small-intestinal microsomes exhibited relatively higher activity toward long-side-chain phthalates. Pancreatic microsomes showed high activity toward DEHP and DBP. Liver microsomal hydrolase activity toward DMP was markedly inhibited by bis(4-nitrophenyl)phosphate, and could be extracted with Triton X-100. The activity toward DBP and DEHP was partly inhibited by carboxylesterase inhibitor, and was partly solubilized with Triton X-100. Ces1e, Ces1d and Ces1f expressed in COS cells exhibited the highest hydrolase activity toward DBP, showing a similar pattern to that of liver microsomes. Ces1e showed activity towards DMP and DEHP. Pancreatic lipase also hydrolyzed DBP and DEHP. Thus, carboxylesterase and lipase contribute differently to phthalate hydrolysis: short-side-chain phthalates are mainly hydrolyzed by carboxylesterase and long-side-chain phthalates are mainly hydrolyzed by lipase.
ESTHER : Ozaki_2017_Food.Chem.Toxicol_100_217
PubMedSearch : Ozaki_2017_Food.Chem.Toxicol_100_217
PubMedID: 28007454

Title : Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase - Hvorecny_2017_Structure_25_697
Author(s) : Hvorecny KL , Bahl CD , Kitamura S , Lee KSS , Hammock BD , Morisseau C , Madden DR
Ref : Structure , 25 :697 , 2017
Abstract : Pseudomonas aeruginosa secretes an epoxide hydrolase with catalytic activity that triggers degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and perturbs other host defense networks. Targets of this CFTR inhibitory factor (Cif) are largely unknown, but include an epoxy-fatty acid. In this class of signaling molecules, chirality can be an important determinant of physiological output and potency. Here we explore the active-site chemistry of this two-step alpha/beta-hydrolase and its implications for an emerging class of virulence enzymes. In combination with hydrolysis data, crystal structures of 15 trapped hydroxyalkyl-enzyme intermediates reveal the stereochemical basis of Cif's substrate specificity, as well as its regioisomeric and enantiomeric preferences. The structures also reveal distinct sets of conformational changes that enable the active site to expand dramatically in two directions, accommodating a surprising array of potential physiological epoxide targets. These new substrates may contribute to Cif's diverse effects in vivo, and thus to the success of P. aeruginosa and other pathogens during infection.
ESTHER : Hvorecny_2017_Structure_25_697
PubMedSearch : Hvorecny_2017_Structure_25_697
PubMedID: 28392259
Gene_locus related to this paper: pseae-PA2934

Title : Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales - Kitamura_2017_PLoS.One_12_e0176571
Author(s) : Kitamura S , Morisseau C , Harris TR , Inceoglu B , Hammock BD
Ref : PLoS ONE , 12 :e0176571 , 2017
Abstract : Recently, dibenzylurea-based potent soluble epoxide hydrolase (sEH) inhibitors were identified in Pentadiplandra brazzeana, a plant in the order Brassicales. In an effort to generalize the concept, we hypothesized that plants that produce benzyl glucosinolates and corresponding isothiocyanates also produce these dibenzylurea derivatives. Our overall aim here was to examine the occurrence of urea derivatives in Brassicales, hoping to find biologically active urea derivatives from plants. First, plants in the order Brassicales were analyzed for the presence of 1, 3-dibenzylurea (compound 1), showing that three additional plants in the order Brassicales produce the urea derivatives. Based on the hypothesis, three dibenzylurea derivatives with sEH inhibitory activity were isolated from maca (Lepidium meyenii) roots. Topical application of one of the identified compounds (compound 3, human sEH IC50 = 222 nM) effectively reduced pain in rat inflammatory pain model, and this compound was bioavailable after oral administration in mice. The biosynthetic pathway of these urea derivatives was investigated using papaya (Carica papaya) seed as a model system. Finally, a small collection of plants from the Brassicales order was grown, collected, extracted and screened for sEH inhibitory activity. Results show that several plants of the Brassicales order could be potential sources of urea-based sEH inhibitors.
ESTHER : Kitamura_2017_PLoS.One_12_e0176571
PubMedSearch : Kitamura_2017_PLoS.One_12_e0176571
PubMedID: 28472063

Title : Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa - Kitamura_2016_J.Med.Chem_59_4790
Author(s) : Kitamura S , Hvorecny KL , Niu J , Hammock BD , Madden DR , Morisseau C
Ref : Journal of Medicinal Chemistry , 59 :4790 , 2016
Abstract : The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. Structural requirements for potency were systematically probed, and interactions between Cif and 1a were characterized by X-ray crystallography. On the basis of these data, new compounds were designed to yield additional hydrogen bonding with residues of the Cif active site. From this effort, three compounds were identified that are 10-fold more potent toward Cif than our first-generation inhibitors and have no detectable thyroid hormone-like activity. These inhibitors will be useful tools to study the pathological role of Cif and have the potential for clinical application.
ESTHER : Kitamura_2016_J.Med.Chem_59_4790
PubMedSearch : Kitamura_2016_J.Med.Chem_59_4790
PubMedID: 27120257
Gene_locus related to this paper: pseae-PA2934

Title : Estimation of the Intestinal Absorption and Metabolism Behaviors of 2- and 3-Monochloropropanediol Esters - Kaze_2016_Lipids_51_913
Author(s) : Kaze N , Watanabe Y , Sato H , Murota K , Kotaniguchi M , Yamamoto H , Inui H , Kitamura S
Ref : Lipids , 51 :913 , 2016
Abstract : The regioisomers of the di- and mono-oleate of monochloropropanediol (MCPD) have been synthesized and subsequently hydrolyzed with pancreatic lipase and pancreatin to estimate the intestinal digestion and absorption of these compounds after their intake. The hydrolysates were analyzed by HPLC using a corona charged aerosol detection system, which allowed for the separation and detection of the different regioisomers of the MCPD esters. The hydrolysates were also analyzed by GC-MS to monitor the free MCPD. The results indicated that the two acyl groups of 2-MCPD-1,3-dioleate were smoothly hydrolyzed by pancreatic lipase and pancreatin to give free 2-MCPD. In contrast, the hydrolysis of 3-MCPD-1,2-dioleate proceeded predominantly at the primary position to produce 3-MCPD-2-oleate. 2-MCPD-1-oleate and 3-MCPD-1-oleate were further hydrolyzed to free 2- and 3-MCPD by pancreatic lipase and pancreatin, although the hydrolysis of 3-MCPD-2-oleate was 80 % slower than that of 3-MCPD-1-oleate. The intestinal absorption characteristics of these compounds were evaluated in vitro using a Caco-2 cell monolayer. The results revealed that the MCPD monooleates, but not the MCPD dioleates, were hydrolyzed to produce the free MCPD in the presence of the Caco-2 cells. The resulting free MCPD permeated the Caco-2 monolayer most likely via a diffusion mechanism because their permeation profiles were independent of the dose. Similar permeation profiles were obtained for 2- and 3-MCPDs.
ESTHER : Kaze_2016_Lipids_51_913
PubMedSearch : Kaze_2016_Lipids_51_913
PubMedID: 27023203

Title : Hydrolytic metabolism of phenyl and benzyl salicylates, fragrances and flavoring agents in foods, by microsomes of rat and human tissues - Ozaki_2015_Food.Chem.Toxicol_86_116
Author(s) : Ozaki H , Sugihara K , Tamura Y , Fujino C , Watanabe Y , Uramaru N , Sone T , Ohta S , Kitamura S
Ref : Food & Chemical Toxicology , 86 :116 , 2015
Abstract : Salicylates are used as fragrance and flavor ingredients for foods, as UV absorbers and as medicines. Here, we examined the hydrolytic metabolism of phenyl and benzyl salicylates by various tissue microsomes and plasma of rats, and by human liver and small-intestinal microsomes. Both salicylates were readily hydrolyzed by tissue microsomes, predominantly in small intestine, followed by liver, although phenyl salicylate was much more rapidly hydrolyzed than benzyl salicylate. The liver and small-intestinal microsomal hydrolase activities were completely inhibited by bis(4-nitrophenyl)phosphate, and could be extracted with Triton X-100. Phenyl salicylate-hydrolyzing activity was co-eluted with carboxylesterase activity by anion exchange column chromatography of the Triton X-100 extracts of liver and small-intestinal microsomes. Expression of rat liver and small-intestinal isoforms of carboxylesterase, Ces1e and Ces2c (AB010632), in COS cells resulted in significant phenyl salicylate-hydrolyzing activities with the same specific activities as those of liver and small-intestinal microsomes, respectively. Human small-intestinal microsomes also exhibited higher hydrolyzing activity than liver microsomes towards these salicylates. Human CES1 and CES2 isozymes expressed in COS cells both readily hydrolyzed phenyl salicylate, but the activity of CES2 was higher than that of CES1. These results indicate that significant amounts of salicylic acid might be formed by microsomal hydrolysis of phenyl and benzyl salicylates in vivo. The possible pharmacological and toxicological effects of salicylic acid released from salicylates present in commercial products should be considered.
ESTHER : Ozaki_2015_Food.Chem.Toxicol_86_116
PubMedSearch : Ozaki_2015_Food.Chem.Toxicol_86_116
PubMedID: 26321725

Title : Potent natural soluble epoxide hydrolase inhibitors from Pentadiplandra brazzeana baillon: synthesis, quantification, and measurement of biological activities in vitro and in vivo - Kitamura_2015_PLoS.One_10_e0117438
Author(s) : Kitamura S , Morisseau C , Inceoglu B , Kamita SG , De Nicola GR , Nyegue M , Hammock BD
Ref : PLoS ONE , 10 :e0117438 , 2015
Abstract : We describe here three urea-based soluble epoxide hydrolase (sEH) inhibitors from the root of the plant Pentadiplandra brazzeana. The concentration of these ureas in the root was quantified by LC-MS/MS, showing that 1, 3-bis (4-methoxybenzyl) urea (MMU) is the most abundant (42.3 mug/g dry root weight). All of the ureas were chemically synthesized, and their inhibitory activity toward recombinant human and recombinant rat sEH was measured. The most potent compound, MMU, showed an IC50 of 92 nM via fluorescent assay and a Ki of 54 nM via radioactivity-based assay on human sEH. MMU effectively reduced inflammatory pain in a rat nociceptive pain assay. These compounds are among the most potent sEH inhibitors derived from natural sources. Moreover, inhibition of sEH by these compounds may mechanistically explain some of the therapeutic effects of P. brazzeana.
ESTHER : Kitamura_2015_PLoS.One_10_e0117438
PubMedSearch : Kitamura_2015_PLoS.One_10_e0117438
PubMedID: 25659109

Title : Transesterification of a series of 12 parabens by liver and small-intestinal microsomes of rats and humans - Fujino_2014_Food.Chem.Toxicol_64_361
Author(s) : Fujino C , Watanabe Y , Uramaru N , Kitamura S
Ref : Food & Chemical Toxicology , 64 :361 , 2014
Abstract : Hydrolytic transformation of parabens (4-hydroxybenzoic acid esters; used as antibacterial agents) to 4-hydroxybenzoic acid and alcohols by tissue microsomes is well-known both in vitro and in vivo. Here, we investigated transesterification reactions of parabens catalyzed by rat and human microsomes, using a series of 12 parabens with C1-C12 alcohol side chains. Transesterification of parabens by rat liver and small-intestinal microsomes occurred in the presence of alcohols in the microsomal incubation mixture. Among the 12 parabens, propylparaben was most effectively transesterified by rat liver microsomes with methanol or ethanol, followed by butylparaben. Relatively low activity was observed with longer-side-chain parabens. In contrast, small-intestinal microsomes exhibited higher activity towards moderately long side-chain parabens, and showed the highest activity toward octylparaben. When parabens were incubated with liver or small-intestinal microsomes in the presence of C1-C12 alcohols, ethanol and decanol were most effectively transferred to parabens by rat liver microsomes and small-intestinal microsomes, respectively. Human liver and small-intestinal microsomes also exhibited significant transesterification activities with different substrate specificities, like rat microsomes. Carboxylesterase isoforms, CES1b and CES1c, and CES2, exhibited significant transesterification activity toward parabens, and showed similar substrate specificity to human liver and small-intestinal microsomes, respectively.
ESTHER : Fujino_2014_Food.Chem.Toxicol_64_361
PubMedSearch : Fujino_2014_Food.Chem.Toxicol_64_361
PubMedID: 24355169

Title : Comparative study of the hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by microsomes of various rat and human tissues - Ozaki_2013_Xenobiotica_43_1064
Author(s) : Ozaki H , Sugihara K , Watanabe Y , Fujino C , Uramaru N , Sone T , Ohta S , Kitamura S
Ref : Xenobiotica , 43 :1064 , 2013
Abstract : Abstract 1. Hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by various tissue microsomes and plasma of rats, as well as human liver and small-intestinal microsomes, was investigated and the structure-metabolic activity relationship was examined. 2. Rat liver microsomes showed the highest activity toward parabens, followed by small-intestinal and lung microsomes. Butylparaben was most effectively hydrolyzed by the liver microsomes, which showed relatively low hydrolytic activity towards parabens with shorter and longer alkyl side chains. 3. In contrast, small-intestinal microsomes exhibited relatively higher activity toward longer-side-chain parabens, and showed the highest activity towards heptylparaben. 4. Rat lung and skin microsomes showed liver-type substrate specificity. Kidney and pancreas microsomes and plasma of rats showed small-intestinal-type substrate specificity. 5. Liver and small-intestinal microsomal hydrolase activity was completely inhibited by bis(4-nitrophenyl)phosphate, and could be extracted with Triton X-100. Ces1e and Ces1d isoforms were identified as carboxylesterase isozymes catalyzing paraben hydrolysis by anion exchange column chromatography of Triton X-100 extract from liver microsomes. 6. Ces1e and Ces1d expressed in COS cells exhibited significant hydrolase activities with the same substrate specificity pattern as that of liver microsomes. Small-intestinal carboxylesterase isozymes Ces2a and Ces2c expressed in COS cells showed the same substrate specificity as small-intestinal microsomes, being more active toward longer-alkyl-side-chain parabens. 7. Human liver microsomes showed the highest hydrolytic activity toward methylparaben, while human small-intestinal microsomes showed a broadly similar substrate specificity to rat small-intestinal microsomes. Human CES1 and CES2 isozymes showed the same substrate specificity patterns as human liver and small-intestinal microsomes, respectively.
ESTHER : Ozaki_2013_Xenobiotica_43_1064
PubMedSearch : Ozaki_2013_Xenobiotica_43_1064
PubMedID: 23742084

Title : The in vitro metabolism of a pyrethroid insecticide, permethrin, and its hydrolysis products in rats - Nakamura_2007_Toxicology_235_176
Author(s) : Nakamura Y , Sugihara K , Sone T , Isobe M , Ohta S , Kitamura S
Ref : Toxicology , 235 :176 , 2007
Abstract : The in vitro metabolism of permethrin and its hydrolysis products in rats was investigated. Cis- and trans-permethrin were mainly hydrolyzed by liver microsomes, and also by small-intestinal microsomes of rats. trans-Permethrin was much more effectively hydrolyzed than the cis-isomer. When NADPH was added to the incubation mixture of the liver microsomes, three metabolites, 3-phenoxybenzyl alcohol (PBAlc), 3-phenoxybenzaldehyde (PBAld) and 3-phenoxybenzoic acid (PBAcid), were formed. However, only PBAlc was formed by rat liver microsomes in the absence of cofactors. The microsomal activities of rat liver and small intestine were inhibited by bis-p-nitrophenyl phosphate, an inhibitor of carboxylesterase (CES). ES-3 and ES-10, isoforms of the CES 1 family, exhibited significant hydrolytic activities toward trans-permethrin. When PBAlc was incubated with rat liver microsomes in the presence of NADPH, PBAld and PBAcid were formed. The NADPH-linked oxidizing activity was inhibited by SKF 525-A. Rat recombinant cytochrome P450, CYP 2C6 and 3A1, exhibited significant oxidase activities with NADPH. When PBAld was incubated with the microsomes in the presence of NADPH, PBAcid was formed. CYP 1A2, 2B1, 2C6, 2D1 and 3A1 exhibited significant oxidase activities in this reaction. Thus, permethrin was hydrolyzed by CES, and PBAlc formed was oxidized to PBAld and PBAcid by the cytochrome P450 system in rats.
ESTHER : Nakamura_2007_Toxicology_235_176
PubMedSearch : Nakamura_2007_Toxicology_235_176
PubMedID: 17451859

Title : Whole-body metabolism of the organophosphorus pesticide, fenthion, in goldfish, Carassius auratus - Kitamura_2000_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_126_259
Author(s) : Kitamura S , Kadota T , Yoshida M , Jinno N , Ohta S
Ref : Comparative Biochemistry & Physiology C Toxicol Pharmacol , 126 :259 , 2000
Abstract : The in vivo metabolism of fenthion, an organophosphorus pesticide, and its sulfoxide (fenthion sulfoxide) was examined in goldfish (Carassius auratus). When goldfish were administered fenthion i.p. at a dose of 100 mg/kg, two metabolites were isolated from the tank water. They were identified as fenthion sulfoxide and fenthion oxon, in which > P = S of fenthion is transformed to > P = O, by comparing their mass and UV spectra, and their behavior in HPLC and TLC, with those of authentic standards. However, fenthion sulfone was not detected as a metabolite. The amounts of fenthion, fenthion sulfoxide and fenthion oxon excreted within 4 days were 2.7, 3.4 and 2.5%, of the initial dose of fenthion, respectively. Unchanged fenthion was detected in the body of the fish to the extent of 42-50% of the dose after 10 days, but fenthion sulfoxide and fenthion oxon showed very low concentrations. When fenthion sulfoxide was administered to the fish, about 70% of the dose was excreted unchanged into the tank water within 24 h, but little of the reduced compound, fenthion, was found. In contrast, fenthion was detected at 2.1% of dose in the body of goldfish as a metabolite of fenthion sulfoxide. The fact that fenthion is metabolized to the toxic oxon form in fish presumably has environmental and health implication for its use as a pesticide.
ESTHER : Kitamura_2000_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_126_259
PubMedSearch : Kitamura_2000_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_126_259
PubMedID: 11048676