Kazumi Sugihara

Hiroshima International University, Hirosima, Hiroshima, Japan

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Publications (93)178.81 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes. Copyright © 2014. Published by Elsevier Inc.
    Toxicology and Applied Pharmacology 12/2014; · 3.63 Impact Factor
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    ABSTRACT: Hepatotoxicity induced by the metabolic activation of drugs is a major concern in drug discovery and development. Three-dimensional (3-D) cultures of hepatocyte spheroids may be superior to monolayer cultures for evaluating drug metabolism and toxicity because hepatocytes in spheroids maintain the expression of various metabolizing enzymes and transporters, such as cytochrome P450 (CYP). In this study, we examined the hepatotoxicity due to metabolic activation of acetaminophen (APAP) using fluorescent indicators of cell viability and intracellular levels of glutathione (GSH) in rat hepatocyte spheroids grown on micro-space cell culture plates. The mRNA expression levels of some drug-metabolizing enzymes were maintained during culture. Additionally, this culture system was compatible with microfluorometric imaging under confocal laser scanning microscopy. APAP induced a decrease in intracellular ATP at 10 mM, which was blocked by the CYP inhibitor 1-aminobenzotriazole (ABT). APAP (10 mM, 24 h) decreased the levels of both intracellular ATP and GSH, and GSH-conjugated APAP (APAP-GSH) were formed. All three effects were blocked by ABT, confirming a contribution of APAP metabolic activation by CYP to spheroid toxicity. Fluorometric imaging of hepatocyte spheroids on micro-space cell culture plates may allow the screening of drug-induced hepatotoxicity during pharmaceutical development.
    Toxicology in Vitro 05/2014; · 3.21 Impact Factor
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    ABSTRACT: Permethrin is a widely applied broad-spectrum pyrethroid insecticide that consists of a mixture of cis- and trans-isomers. We examined the changes of estrogenic and anti-androgenic activities resulting from metabolism of the isomers. Both cis- and trans-permethrin were hydrolyzed to 3-phenoxybenzyl alcohol (PBAlc) by rat liver microsomes, but the extent of hydrolysis of trans-permethrin was much greater than that of the cis-isomer. In the presence of NADPH, PBAlc was further transformed to 4'-hydroxylated PBAlc (4'-OH PBAlc), 3-phenoxybenzaldehyde (PBAld) and 3-phenoxybenzoic acid (PBAcid). cis-Permethrin, but not trans-permethrin, also afforded its 4'-hydroxylated derivative (4'-OH cis-permethrin). trans-Permethrin was an anti-androgen, but also showed weak estrogenic activity, while cis-permethrin was a weak estrogen and a weak anti-androgen. After incubation with rat liver microsomes in the presence of NADPH, cis-permethrin but not trans-permethrin was metabolically activated for estrogenic activity. On the other hand, estrogenic activity of trans-permethrin was not changed, but its anti-androgenic activity was enhanced after incubation. 4'-OH PBAlc and PBAlc showed estrogenic activity, while PBAld and PBAlc showed anti-androgenic activity. PBAcid showed neither activity. 4'-OH cis-permethrin showed both estrogenic and anti-androgenic activities. Overall, our results indicate that permethrin is metabolically activated for estrogenic and anti-androgen activities, and the microsomal transformation of permethrin to 4'-OH cis-permethrin, 4'-OH PBAlc and PBAlc contributes to the both metabolic activations.
    Environmental toxicology and pharmacology. 03/2014; 37(3):996-1005.
  • Toxicology in Vitro. 01/2014; 28(6):1176–1182.
  • Shigeyuki Kitamura, Kazumi Sugihara
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    ABSTRACT: Abstract 1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.
    Xenobiotica 12/2013; · 2.10 Impact Factor
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    ABSTRACT: There have been many concerns expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals including polychlorinated biphenyls and polybrominated diphenyl ethers (PBDEs), since thyroid hormones play crucial roles in normal vertebrate development. A vast amount of PBDEs have been used as flame retardants for the last two decades and our environment has been contaminated with them. Some PBDEs, especially hydroxylated PBDEs, reportedly show an affinity to the thyroid hormone receptor (TR) and act as thyroid hormone agonists, but in other studies they were reported to inhibit the actions of thyroid hormones. Therefore, in the present study, we investigated the binding affinities of PBDEs and their metabolites to TR and their ability to induce thyroid hormone-responsive transcription using luciferase reporter gene assays in two different cell lines, a pituitary cell line, MtT/E-2, and Chinese hamster ovary (CHO) cells. The binding assay showed that many of the examined PBDEs have significant affinity to TR. Interestingly, some of these PBDEs, such as 4'OH-BDE-17 and 2'OH-BDE-28, acted as agonists in the reporter gene assay in MtT/E-2 cells, while they acted as antagonists in CHO cells. Our results demonstrated that whether PBDEs and their metabolites are TR agonists or antagonists depends on the cell type used in the assay, which may suggest that the thyroid hormone-disrupting actions of PBDEs differ among target tissues or species.
    Toxicology Letters 09/2013; · 3.36 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the possible influence of halogenated compounds on thyroid hormone metabolism via inhibition of iodotyrosine deiodinase (IYD) activity. The structure-activity relationships of 44 halogenated compounds for IYD-inhibitory activity were examined in vitro using microsomes of HEK-293T cells expressing recombinant human IYD. The compounds examined were 17 polychlorinated biphenyls (PCBs), 15 polybrominated diphenyl ethers (PBDEs), two agrichemicals, five antiparasitics, two pharmaceuticals and three food colorants. Among them, 25 halogenated phenolic compounds inhibited IYD activity at the concentration of 1×10(-4)M or 6×10(-4)M. Rose bengal was the most potent inhibitor, followed by erythrosine B, phloxine B, benzbromarone, 4'-hydroxy-2,2',4-tribromodiphenyl ether, 4-hydroxy-2,3',3,4'-tetrabromodiphenyl ether, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl, 4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether, triclosan, and 4-hydroxy-2,2',3,4',5-pentabromodiphenyl ether. However, among PCBs and PBDEs without a hydroxyl group, including their methoxylated metabolites, none inhibited IYD activity. These results suggest that halogenated compounds may disturb thyroid hormone homeostasis via inhibition of IYD, and that the structural requirements for IYD-inhibitory activity include halogen atom and hydroxyl group substitution on a phenyl ring.
    Toxicology 09/2013; · 3.75 Impact Factor
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    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.
    Xenobiotica 06/2013; · 2.10 Impact Factor
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    ABSTRACT: Abstract 1. Human chimeric mice (h-PXB mice) having humanized liver, constructed by transplantation of human hepatocytes, were evaluated as an experimental model for predicting human drug metabolism. Metabolism of zaleplon in h-PXB mice was compared with that in rat chimeric mice (r-PXB mice) constructed by transplantation of rat hepatocytes. 2. Zaleplon is metabolized to 5-oxo-zaleplon by aldehyde oxidase and to desethyl-zaleplon by cytochrome P450 (CYP3A4) in rat and human liver preparations. 3. Liver S9 fraction of h-PXB mice metabolized zaleplon to 5-oxo-zaleplon and desethyl-zaleplon in similar amounts. However, liver S9 fractions of r-PXB and control (urokinase-type plasminogen activator-transgenic severe combined immunodeficient) mice predominantly metabolized zaleplon to desethyl-zaleplon. 5-Oxo-zaleplon was detected as a minor metabolite. 4. Oxidase activity of h-PXB mouse liver cytosol toward zaleplon was about 10-fold higher than that of r-PXB or control mice. In contrast, activities for desethyl-zaleplon formation were similar in liver microsomes from these mice, as well as rat and human liver microsomes. 5. In vivo, the level of 5-oxo-zaleplon in plasma of h-PXB mice was about 7-fold higher than that in r-PXB or control mice, in agreement with the in vitro data. Thus, aldehyde oxidase in h-PXB mice functions as human aldehyde oxidase, both in vivo and in vitro. 6. In contrast, the plasma level of desethyl-zaleplon in r-PXB and control mice was higher than that in h-PXB mice. 7. These results suggest h-PXB mice with humanized liver could be a useful experimental model to predict aldehyde oxidase- and CYP3A4-mediated drug metabolism in humans.
    Xenobiotica 05/2013; · 2.10 Impact Factor
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    ABSTRACT: The in vivo and in vitro metabolism of the sedative-hypnotic agent Zaleplon (ZAL) to 5-hydroxylated ZAL (5-oxo-ZAL) and N-desethylated ZAL (desethyl-ZAL) was studied in four strains of rats. Incubation of ZAL with liver microsomes afforded desethyl-ZAL via cytochrome P450-catalyzed reaction, with little strain difference. In contrast, incubation of ZAL with liver cytosol afforded 5-oxo-ZAL with marked strain differences. ZAL hydroxylase activity was well correlated with aldehyde oxidase activity in these strains. The highest level of 5-oxo-ZAL and the highest activity of aldehyde oxidase were observed in cytosol from Sea:SD rats, followed by Jcl:SD rats, while Crj:SD and WKA/Sea rats showed low levels. When ZAL was administered to Sea:SD and WKA/Sea rats, both 5-oxo-ZAL and desethyl-ZAL were detected in blood as the major in vivo metabolites. However, the concentration of 5-oxo-ZAL was far higher in Sea:SD rats than in WKA/Sea rats, while that of desethyl-ZAL was far lower in Sea:SD rats. The levels of 5-oxo-ZAL in blood were closely correlated with the strain differences of cytosolic ZAL hydroxylase activity and benzaldehyde oxidase activity. Our results indicate that variability in the formation of 5-oxo-ZAL from ZAL in vivo in various strains of rats is primarily due to strain differences of hepatic aldehyde oxidase activity.
    Drug Metabolism and Pharmacokinetics 01/2013; · 2.07 Impact Factor
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    ABSTRACT: In order to investigate the effect of sunlight on the persistence and ecotoxicity of pharmaceuticals contaminating the aquatic environment, we exposed nine pharmaceuticals (acetaminophen (AA), amiodarone (AM), dapsone (DP), dexamethasone (DX), indomethacin (IM), naproxen (NP), phenytoin (PH), raloxifene (RL), and sulindac (SL)) in aqueous media to sunlight and to ultraviolet (UV) irradiation at 254, 302 or 365 nm (UV-C, UV-B or UV-A, respectively). Degradation of the pharmaceuticals was monitored by means of high-performance liquid chromatography (HPLC). Sunlight completely degraded AM, DP and DX within 6 hr, and partly degraded the other pharmaceuticals, except AA and PH, which were not degraded. Similar results were obtained with UV-B, while UV-A was less effective (both UV-A and -B are components of sunlight). All the pharmaceuticals were photodegraded by UV-C, which is used for sterilization in sewage treatment plants. Thus, the photodegradation rates of pharmaceuticals are dependent on both chemical structure and the wavelength of UV exposure. Toxicity assay using the luminescent bacteria test (ISO11348) indicated that UV irradiation reduced the toxicity of some pharmaceuticals to aquatic organisms by decreasing their amount (photodegradation) and increased the toxicity of others by generating toxic photoproduct(s). These results indicate the importance of investigating not only parent compounds, but also photoproducts in the risk assessment of pharmaceuticals in aquatic environments.
    The Journal of Toxicological Sciences 01/2013; 38(2):215-223. · 1.38 Impact Factor
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    ABSTRACT: This study was focused on photodegradation of acetaminophen (AA) exposed to ultraviolet (UV) irradiation at 254 nm delivered by a system similar to that used for sterilization in sewage treatment plants. The degradation of AA during irradiation for up to 96 h was monitored by means of high-performance liquid chromatography (HPLC). Based on the mass/charge ratio (m/z) of the protonated ion and the mass fragmentation pattern in electrospray ionization time-of-flight mass spectrometry (ESI-TOF/MS/MS), the photoproduct was identified as 1-(2-amino-5-hydroxyphenyl)ethanone (1). Examination of toxicity by means of a luminescent bacteria test (ISO11348) indicated that AA solution was nontoxic, whereas photo-exposed AA solution was toxic (EC50: 29.46 mg/L). The toxicity of synthetic compound 1 was shown to account for a substantial part of the toxicity of photo-exposed AA. These results indicate the importance of investigating not only parent compounds, but also photoproducts the risk assessment of pharmaceuticals in aquatic environments.
    Journal of Photochemistry and Photobiology A Chemistry 12/2012; 249:29–35. · 2.29 Impact Factor
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    ABSTRACT: 1. When benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) was incubated with liver microsomes of untreated rats in the presence of NADPH, the 5-hydroxylated metabolite, 2,5-dihydroxy-4-methoxybenzophenone (5-OH-BP-3), was formed as a major novel metabolite of BP-3. The 4-desmethylated metabolite, 2,4-dihydroxybenzophenone (2,4-diOH-BP), previously reported as the major in vivo metabolite of BP-3, was also detected. However, the amount of 5-OH-BP-3 formed in vitro was about the same as that of 2,4-diOH-BP. 2. The oxidase activity affording 5-OH-BP-3 was inhibited by SKF 525-A and ketoconazole, and partly by quinidine and sulfaphenazole. The oxidase activity affording 2,4-diOH-BP was inhibited by SKF 525-A, ketoconazole and α-naphthoflavone, and partly by sulfaphenazole. 3. The oxidase activity affording 5-OH-BP-3 was enhanced in liver microsomes of dexamethasone-, phenobarbital- and 3-methylcholanthrene-treated rats. The activity affording 2,4-diOH-BP was enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats. 4. When examined recombinant rat cytochrome P450 isoforms catalyzing the metabolism of BP-3, 5-hydroxylation was catalyzed by P450 3A2, 1A1, 2B1, 2C6 and 2D1, while 4-desmethylation was catalyzed by P450 2C6 and 1A1.
    Xenobiotica 11/2012; · 2.10 Impact Factor
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    ABSTRACT: Prediction of human drug metabolism is important for drug development. Recently, the number of new drug candidates metabolized by not only cytochrome P450 (P450) but also non-P450 has been increasing. It is necessary to consider species differences in drug metabolism between humans and experimental animals. We examined species differences of drug metabolism, especially between humans and rats, for ibuprofen and (S)-naproxen as non-steroidal anti-inflammatory drugs (NSAIDs), which are metabolized by P450 and UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and amino acid N-acyltransferase for taurine conjugation in liver, using human chimeric mice (h-PXB mice) repopulated with human hepatocytes and rat chimeric mice (r-PXB mice) transplanted with rat hepatocytes. We performed the direct comparison of excretory metabolites in urine between h-PXB mice and reported data for humans as well as between r-PXB mice and rats after administration of ibuprofen and (S)-naproxen. Good agreement for urinary metabolites (% of dose) was observed not only between humans and h-PXB mice but also between rats and r-PXB mice. Therefore, the metabolic profiles in humans and rats reflected those in h-PXB mice and r-PXB mice. Our results indicated that h-PXB mice should be helpful for predicting the quantitative metabolic profiles of drugs mediated by P450 and non-P450 in liver, and r-PXB mice should be helpful for evaluation of species differences in these metabolic enzymes.
    Drug metabolism and disposition: the biological fate of chemicals 08/2012; · 3.74 Impact Factor
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    ABSTRACT: Aldehyde oxidase (AO) plays a role in metabolizing many drugs, such as methotrexate and 6-mercaptopurine. We previously showed that AO activity in rat liver rapidly increases from birth, reaching a plateau within 4 weeks, and is regulated at the protein expression level. However, developmental changes of AO activity and protein expression in human liver have not been reported. Here, we investigated the developmental changes and variability of AO in 16 human livers (13 children ranging from 13 days to 12 years old and 3 adults, 17, 34 and 45 years old). Young children (13 days to 4 months after birth) showed little liver AO activity, evaluated in terms of the activities for oxidation of N-1-methylnicotinamide to N-1-methyl-2-pyridone-5-carboxamide and N-1-methyl-4-pyridone-3-carboxamide in liver cytosol. However, these oxidase activities were markedly increased after 4 months, reaching the adult level by about 2 years of age. The AO band density in immunoblotting analysis was well correlated with the AO activity among all subjects (p < 0.01, r(2) = 0.771). Therefore, AO activity in the liver of young children is regulated at the AO protein expression level. Thus, as in rats, the AO activity in humans rapidly increases soon after birth, and is regulated at the protein expression level.
    Drug Metabolism and Pharmacokinetics 03/2012; 27(5):543-7. · 2.07 Impact Factor
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    ABSTRACT: A number of environmental chemicals have been reported to exhibit thyroid hormone-like activity. Since thyroid hormones play a crucial role in development, it is important to identify chemicals in the environment that are capable of endocrine disruption of thyroid hormone homeostasis. In order to detect thyroid hormone-like activity, the growth of pituitary cell lines has been commonly used as a sensitive marker, albeit with limited specificity to thyroid hormones. Reporter gene assays using the thyroid hormone responsive element (TRE) connected to the luciferase reporter gene have also been developed. Thus far however, this type of assay appears to have limited sensitivity compared to cell growth assays. In the present study, we developed a highly sensitive TRE reporter gene assay by using a pituitary cell line, MtT/E-2, and by culturing cells in a serum-free medium. Our assay was developed in order to detect T3 activity at a concentration of 10(-11)M. This assay identified thyroid hormone-like activity from the antiarrhythmic drug, amiodarone, and from three anti-parasitic drugs, bithionol, closantel and rafoxanide, all commonly used in veterinary medicine. Thyroid hormone-like activity of these compounds was further confirmed by the induction of BCL3 gene expression in MtT/E-2, which is known to be regulated by thyroid hormones. Our improved assay was proved to be a sensitive tool for assessing thyroid hormone-like activity of environmental chemicals.
    Toxicology Letters 01/2012; 208(1):30-5. · 3.36 Impact Factor
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    ABSTRACT: Polybrominated diphenyl ethers (PBDEs) have been used in a variety of consumer products such as flame retardants and recently have been known to be widespread environmental pollutants, which probably affect biological functions of mammalian cells. However, the risk posed by PBDE metabolites has not been clarified. Our previous study suggested that bisphenol A (BPA), an endocrine-disrupting chemical, binds to protein disulfide isomerase (PDI) and inhibits its activity. PDI is an isomerase enzyme in the endoplasmic reticulum and facilitates the formation or cleavage of disulfide bonds. PDI consists of a, b, b', and a' domains and the c region, with the a and a' domains having isomerase active sites. In the present study, we tested the effects of 10 kinds of PBDE compounds and their metabolites on PDI. OH-PBDEs specifically inhibited the isomerase activity of PDI, with 4'-OH-PBDE more effective than 2' (or 2)-OH-PBDEs. 4'-OH-PBDE inhibited the isomerase activity of the b'a'c fragment but not that of ab and a'c, suggesting that the b' domain of PDI is essential for the inhibition by 4'-OH-PBDE. We also investigated the effects of these chemicals on the production of growth hormone (GH) in GH3 cells. In GH3 cells, levels of mRNA and protein of GH stimulated by T(3) were reduced by 4'-OH-PBDE and 4'-MeO-PBDE. The reduction in GH expression caused by these compounds was not changed by the overexpression or knockdown of PDI in GH3 cells, while these manipulations of PDI levels significantly suppressed the expression of GH. These results suggest that the biological effects of PBDEs differed depending on their brominated and hydroxylated positions.
    Chemical Research in Toxicology 12/2011; 25(3):656-63. · 4.19 Impact Factor
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    ABSTRACT: Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. Direct comparison between in vitro intrinsic clearance (CL(int,in vitro)) in PXB mice hepatocytes and in vivo intrinsic clearance (CL(int,in vivo)) in humans, calculated based on a well stirred model, showed a moderate correlation (r² = 0.475, p = 0.009). However, when CL(int,in vivo) values in humans and PXB mice were compared similarly, there was a good correlation (r² = 0.754, p = 1.174 × 10⁻⁴). Elimination half-life (t(1/2)) after intravenous administration also showed a good correlation (r² = 0.886, p = 1.506 × 10⁻⁴) between humans and PXB mice. The rank order of CL and t(1/2) in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.
    Drug metabolism and disposition: the biological fate of chemicals 11/2011; 40(2):322-8. · 3.74 Impact Factor
  • Anticholinesterase Pesticides: Metabolism, Neurotoxicity, and Epidemiology, 03/2011: pages 189 - 202; , ISBN: 9780470640500
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    ABSTRACT: Aldehyde oxidase (AO) plays an important role in metabolizing antitumor and antiviral drugs, including methotrexate, cyclophosphamide and acyclovir. Green tea and its catechins have been shown to modulate the activities of various xenobiotic-metabolizing cytochrome P450 species, both in vivo and in vitro, but their effect on AO has not been studied. Therefore, we evaluated the effect of tea beverages on AO activity in rat and human liver cytosol. We also investigated the influence of several catechins on AO activity in rat liver cytosol. AO activity was evaluated in terms of oxidation of N-1-methylnicotinamide to N-1-methyl-2-pyridone-5-carboxamide and N-1-methyl-4-pyridone-3-carboxamide. Bottled green tea beverages at 10% (vol/vol) inhibited AO activity by 90.0-93.5%, while at 1.0% (vol/vol), they reduced AO activity by 73.9-90.0%. At 0.1% (vol/vol), green tea II and III, which have high contents of catechins and their derivatives, inhibited AO activity by 24.3% and 38.8%, respectively. Bottled mineral water had no effect. AO activity was inhibited potently by epicatechin and epicatechin gallate. These results indicate that the AO-inhibitory activity of tea beverages is predominantly due to catechins and their derivatives. Thus, consumption of tea beverages may cause a decrease of AO activity, which may result in reduced clearance of drugs that are AO substrates.
    Drug Metabolism and Pharmacokinetics 11/2010; 26(1):94-101. · 2.07 Impact Factor

Publication Stats

1k Citations
178.81 Total Impact Points


  • 2009–2014
    • Hiroshima International University
      • Faculty of Pharmaceutical Science
      Hirosima, Hiroshima, Japan
    • Hokkaido Institute of Public Health
      Edo, Tōkyō, Japan
  • 1999–2013
    • Hiroshima University
      • • Graduate School of Biomedical and Health Sciences
      • • Faculty of Pharmaceutical Sciences
      • • Institute of Pharmaceutical Sciences
      Hiroshima-shi, Hiroshima-ken, Japan
  • 2008
    • Nihon Pharmaceutical University
      Komoro, Nagano, Japan
  • 2001
    • Tohoku University
      • Department of Chemistry