研究者詳細 - 米澤　淳

論文 - 米澤　淳

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Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Foley A.R., Menezes M.P., Pandraud A., Gonzalez M.A., Al-Odaib A., Abrams A.J., Sugano K., Yonezawa A., Manzur A.Y., Burns J., Hughes I., McCullagh B.G., Jungbluth H., Lim M.J., Lin J.P., Megarbane A., Urtizberea J.A., Shah A.H., Antony J., Webster R., Broomfield A., Ng J., Mathew A.A., O'Byrne J.J., Forman E., Scoto M., Prasad M., O'Brien K., Olpin S., Oppenheim M., Hargreaves I., Land J.M., Wang M.X., Carpenter K., Horvath R., Straub V., Lek M., Gold W., Farrell M.O., Brandner S., Phadke R., Matsubara K., McGarvey M.L., Scherer S.S., Baxter P.S., King M.D., Clayton P., Rahman S., Reilly M.M., Ouvrier R.A., Christodoulou J., Züchner S., Muntoni F., Houlden H.

Brain （Brain） 137 （ 1 ） 44 - 56 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00068950

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms. © 2013 The Author.

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Safety and Efficacy of Sustained Release of Basic Fibroblast growth Factor Using Biodegradable Gelatin Hydrogel in Patients With Critical Limb Ischemia

Motoyuki Kumagai, Akira Marui, Yasuhiko Tabata, Takahide Takeda, Masaya Yamamoto, Atsushi Yonezawa, Shiro Tanaka, Shigeki Yanagi, Toshiko Ito-Ihara, Takafumi Ikeda, Toshinori Murayama, Satoshi Teramukai, Toshiya Katsura, Kazuo Matsubara, Koji Kawakami, Masayuki Yokode, Akira Shimizu, Ryuzo Sakata

CIRCULATION （LIPPINCOTT WILLIAMS & WILKINS） 128 （ 22 ） 16154.0 2013年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-7322

Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models

Nakanishi H., Yonezawa A., Matsubara K., Yano I.

European Journal of Pharmacology （European Journal of Pharmacology） 710 （ 1-3 ） 20 - 28 2013年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00142999

Refractory epilepsy is reportedly associated with an overexpression of ATP-binding cassette transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (Bcrp). In this study, we examined the contribution of Pgp and Bcrp to the brain distribution of 12 antiepileptic drugs (AEDs) in Mdr1a/1b(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice within a therapeutic concentration range. The blood concentrations were sequentially determined, and the brain concentrations were measured at 60 min after intravenous administration. The plasma concentration profiles for each AED in the Mdr1a/1b(-/-) mice were equivalent to those in the wild-type mice. In contrast, the plasma concentration profiles of phenytoin, lamotrigine, topiramate, tiagabine, and levetiracetam in the Mdr1a/1b(-/-)/Bcrp(-/-) mice were significantly lower than the corresponding ones in the wild-type mice. The brain-to-plasma concentration ratio (Kpbrain) values of phenytoin, topiramate, and tiagabine in the Mdr1a/1b(-/-) mice were significantly higher than the corresponding ones in the wild-type mice. In contrast, the Kp brain values of phenobarbital, clobazam, zonisamide, gabapentin, tiagabine, and levetiracetam in the Mdr1a/1b(-/-)/Bcrp(-/-) mice were significantly higher than the corresponding ones in Mdr1a/1b(-/-) mice. The Kpbrain values of the 12 AEDs in the Mdr1a/1b(-/-)/Bcrp(-/-) mice, but not wild-type mice, significantly correlated with the corresponding molecular weight values. These findings suggest that both Pgp and Bcrp restrict brain access for several AEDs. Taken together, information on the contribution of each transporter may be useful in the development of strategic treatments of refractory epilepsy. © 2013 Elsevier B.V.

Novel riboflavin transporter family RFVT/SLC52: Identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52

Yonezawa A., Inui K.

Molecular Aspects of Medicine （Molecular Aspects of Medicine） 34 （ 2-3 ） 693 - 701 2013年04月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 00982997

Riboflavin, a water-soluble vitamin also known as vitamin B2, is essential for normal cellular functions. Riboflavin transporters play important roles in its homeostasis. Recently, three novel riboflavin transporters were identified, and designated as RFT1, RFT2 and RFT3. Because the RFTs did not show similarity to other SLC transporters, and RFT1 and RFT3 are similar in sequence and function, they were assigned into a new SLC family, SLC52. Subsequently, RFT1/GPR172B, RFT3/GPR172A and RFT2/C20orf54 were renamed as RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3, respectively. In this review, we summarize recent findings on the cloning, nomenclature, functional characterization and genetic diseases of RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3. © 2012 Elsevier Ltd. All rights reserved.

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Sodium tauroursodeoxycholate prevents paraquat-induced cell death by suppressing endoplasmic reticulum stress responses in human lung epithelial A549 cells

Omura T., Asari M., Yamamoto J., Oka K., Hoshina C., Maseda C., Awaya T., Tasaki Y., Shiono H., Yonezawa A., Masuda S., Matsubara K., Shimizu K.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 432 （ 4 ） 689 - 694 2013年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006291X

Paraquat is a commonly used herbicide; however, it is highly toxic to humans and animals. Exposure to paraquat causes severe lung damage, leading to pulmonary fibrosis. However, it has not been well clarified as how paraquat causes cellular damage, and there is no established standard therapy for paraquat poisoning. Meanwhile, endoplasmic reticulum stress (ERS) is reported to be one of the causative factors in many diseases, although mammalian cells have a defense mechanism against ERS-induced apoptosis (unfolded protein response). Here, we demonstrated that paraquat changed the expression levels of unfolded protein response-related molecules, resulting in ERS-related cell death in human lung epithelial A549 cells. Moreover, treatment with sodium tauroursodeoxycholate (TUDCA), a chemical chaperone, crucially rescued cells from death caused by exposure to paraquat. These results indicate that paraquat toxicity may be associated with ERS-related molecules/events. Through chemical chaperone activity, treatment with TUDCA reduced paraquat-induced ERS and mildly suppressed cell death. Our findings also suggest that TUDCA treatment represses the onset of pulmonary fibrosis caused by paraquat, and therefore chemical chaperones may have novel therapeutic potential for the treatment of paraquat poisoning. © 2013 Elsevier Inc.

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Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity

Nishihara K., Masuda S., Shinke H., Ozawa A., Ichimura T., Yonezawa A., Nakagawa S., Inui K.I., Bonventre J.V., Matsubara K.

Biochemical Pharmacology （Biochemical Pharmacology） 85 （ 4 ） 570 - 582 2013年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00062952

Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5 mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2 mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury. © 2012 Elsevier Inc.

Involvement of riboflavin transporter RFVT2/Slc52a2 in hepatic homeostasis of riboflavin in mice

Yao Y., Yonezawa A., Yoshimatsu H., Omura T., Masuda S., Matsubara K.

European Journal of Pharmacology （European Journal of Pharmacology） 714 （ 1-3 ） 281 - 287 2013年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 00142999

Riboflavin (vitamin B2) acts as an intermediary during various biochemical oxidation-reduction reactions in the liver. Hepatic riboflavin homeostasis is suggested to be maintained through its transporter(s). Riboflavin transporters, RFVT2/Slc52a2 and RFVT3/Slc52a3, have been identified in rodents. However, the role of each RFVT in the hepatic homeostasis of riboflavin has not yet been fully clarified. In this study, we assessed the contribution of each RFVT to riboflavin uptake into the liver using in vitro and in vivo studies. The uptake of riboflavin by mouse primary hepatocytes increased in a time-dependent and a concentration-dependent manner. Riboflavin transport was independent of extracellular Na+. However, the uptake decreased slightly along with the extracellular pH increases. Real-time PCR analysis revealed that the mRNA level of Slc52α2, or coding for mouse (m)RFVT2, in the mouse liver was 10 times higher than that of Slc52α3 (coding for mRFVT3). The uptake of riboflavin at pH 7.4 by primary hepatocytes was significantly decreased by the transfection of Slc52α2-small interfering RNA (siRNA), but not Slc52α3-siRNA. Furthermore, we also confirmed the contribution of riboflavin transporters in vivo. The riboflavin concentrations in plasma, but not in the liver, were significantly decreased in mice fed on a riboflavin-deficient diet for 8 weeks. The expression of Slc52α2 mRNA was significantly upregulated by riboflavin deprivation. These results strongly suggest that mRFVT2 was involved in hepatic riboflavin homeostasis. © 2013 Elsevier B.V. All rights reserved.

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Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome

Haack T.B., Makowski C., Yao Y., Graf E., Hempel M., Wieland T., Tauer U., Ahting U., Mayr J.A., Freisinger P., Yoshimatsu H., Inui K., Strom T.M., Meitinger T., Yonezawa A., Prokisch H.

Journal of Inherited Metabolic Disease （Journal of Inherited Metabolic Disease） 35 （ 6 ） 943 - 948 2012年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01418955

Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment. © 2012 SSIEM and Springer.

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Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis

Toyama K., Yonezawa A., Masuda S., Osawa R., Hosokawa M., Fujimoto S., Inagaki N., Inui K., Katsura T.

British Journal of Pharmacology （British Journal of Pharmacology） 166 （ 3 ） 1183 - 1191 2012年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00071188

BACKGROUNDS AND PURPOSE Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis. EXPERIMENTAL APPROACH Blood lactate, pH and bicarbonate ion (HCO 3-) levels were evaluated during continuous administration of 3 mg·mL -1 metformin in drinking water using Mate1 knockout (-/-), heterozygous (+/-) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg·kg -1 metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin. KEY RESULTS Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO 3- levels were observed in Mate1 -/- mice, but not in Mate1 +/- mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg·kg -1, p.o.) the hepatic concentration of metformin was markedly higher in Mate1 -/- mice than in Mate1 +/+ mice. CONCLUSION AND IMPLICATIONS MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin-induced lactic acidosis. © 2012 The British Pharmacological Society.

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Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics

Yonezawa A., Inui K.

British Journal of Pharmacology （British Journal of Pharmacology） 164 （ 7 ） 1817 - 1825 2011年12月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 00071188

The renal organic cation transport system mediates the tubular secretion of cationic compounds including drugs, toxins and endogenous metabolites into urine. It consists of a membrane potential-dependent organic cation transporter at the basolateral membrane and an H +/organic cation antiporter at the brush-border membrane. In 2005, human multidrug and toxin extrusion MATE1/SLC47A1 was identified as a mammalian homologue of bacterial NorM. Thereafter, human MATE2-K/SLC47A2 and rodent MATE were found. Functional characterization revealed that MATE1 and MATE2-K were H +/organic cation antiporter, mediating the renal tubular secretion of cationic drugs in cooperation with the basolateral organic cation transporter OCT2. Recently, substrate specificity, transcription mechanisms, structure, polymorphisms, in vivo contributions and clinical outcomes on MATE have been investigated intensively. In this review, we summarize recent findings on MATE1/SLC47A1 and MATE2-K/SLC47A2 and discuss the importance of these transporters to the pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics of cationic drugs. © 2011 The British Pharmacological Society.

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Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B

Ho G., Yonezawa A., Masuda S., Inui K.I., Sim K.G., Carpenter K., Olsen R.K.J., Mitchell J.J., Rhead W.J., Peters G., Christodoulou J.

Human Mutation （Human Mutation） 32 （ 1 ） E1976 - E1984 2011年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10597794

Riboflavin, or vitamin B2, is a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules, required in biological oxidation-reduction reactions. We previously reported a case of a newborn female who had clinical and biochemical features of multiple acyl-CoA dehydrogenation deficiency (MADD), which was corrected by riboflavin supplementation. The mother was then found to be persistently riboflavin deficient, suggesting that a possible genetic defect in riboflavin transport in the mother was the cause of the transient MADD seen in the infant. Two recently-identified riboflavin transporters G protein-coupled receptor 172B (GPR172B or RFT1) and riboflavin transporter 2 (C20orf54 or RFT2) were screened for mutations. Two missense sequence variations, c.209A>G [p.Q70R] and c.886G>A [p.V296M] were found in GPR172B. In vitro functional studies of both missense variations showed that riboflavin transport was unaffected by these variations. Quantitative real-time PCR revealed a de novo deletion in GPR172B spanning exons 2 and 3 in one allele from the mother. We postulate that haploinsufficiency of this riboflavin transporter causes mild riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, resulted in the transient riboflavin-responsive disease seen in her newborn infant. This is the first report of a genetic defect in riboflavin transport in humans. © 2010 Wiley-Liss, Inc.

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Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity

Nakamura T., Yonezawa A., Hashimoto S., Katsura T., Inui K.I.

Biochemical Pharmacology （Biochemical Pharmacology） 80 （ 11 ） 1762 - 1767 2010年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00062952

Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is expressed in the brush-border membrane of renal proximal tubules and mediates the efflux of cationic drugs. In the present study, the role of MATE1 in the nephrotoxicity of cisplatin was investigated in vivo and in vitro. Cisplatin (15. mg/kg) was administered intraperitoneally to wild-type (Mate1(+/+)) and Mate1 knockout (Mate1(-/-)) mice. Lifespan was significantly shorter in Mate1(-/-) mice than Mate1(+/+) mice. Three days after the administration of cisplatin, plasma creatinine and blood urea nitrogen (BUN) levels were increased in both Mate1(+/+) and Mate1(-/-) mice compared with vehicle-treated controls, and creatinine clearance was decreased. Moreover, a significant rise in creatinine and BUN levels was observed in cisplatin-treated Mate1(-/-) mice in comparison to Mate1(+/+) mice. A pharmacokinetic analysis revealed the plasma concentration and renal accumulation of cisplatin to be higher in Mate1(-/-) mice than Mate1(+/+) mice 1. h after a single intravenous administration of cisplatin (0.5. mg/kg). Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone. In experiments in vitro, the cellular uptake of cisplatin was stimulated by the expression of mouse MATE1 as well as organic cation transporters OCT1 and OCT2. In conclusion, MATE1 mediates the efflux of cisplatin and is involved in cisplatin-induced nephrotoxicity. © 2010 Elsevier Inc.

Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: A prospective clinical trial

Nakagawa T., Sakamoto T., Hiraumi H., Kikkawa Y.S., Yamamoto N., Hamaguchi K., Ono K., Yamamoto M., Tabata Y., Teramukai S., Tanaka S., Tada H., Onodera R., Yonezawa A., Inui K.I., Ito J.

BMC Medicine （BMC Medicine） 8 76 2010年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1741-7015

Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL.Methods: Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy.Results: In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015) at 24 weeks. No serious adverse events were observed.Conclusions: Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids. © 2010 Nakagawa et al; licensee BioMed Central Ltd.

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Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain

Yao Y., Yonezawa A., Yoshimatsu H., Masuda S., Katsura T., Inui K.

Journal of Nutrition （Journal of Nutrition） 140 （ 7 ） 1220 - 1226 2010年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223166

We isolated cDNA coding a new human riboflavin transporter (hRFT)3, which exhibits 86.7 and 44.1% amino acid identity with hRFT1 and hRFT2, respectively. It was predicted to have 10 putative membrane-spanning domains. The functional characteristics of hRFT3 were examined and compared with those of its isoforms, hRFT1 and hRFT2. Realtime PCR revealed that hRFT3 mRNA was strongly expressed in the brain and salivary gland. hRFT1 mRNA was strongly expressed in the placenta and small intestine, whereas hRFT2 mRNA was most abundantly expressed in the testis and strongly in the small intestine and prostate. hRFT-mediated uptake of [3H]riboflavin was evaluated using human embryonic kidney 293 cells transiently transfected with the cDNA coding each hRFT. The apparent Michaelis-Menten constants of hRFT1, hRFT2, and hRFT3 for riboflavin were 1.38, 0.98, and 0.33 μmol/L, respectively. The hRFT-mediated [3H] riboflavin uptake was independent of extracellular Na+ and Cl -. Specific uptake of [3H]riboflavin by hRFT2, but not hRFT1 and hRFT3, decreased as extracellular pH was changed from 5.4 to 8.4. The substrate specificities of the hRFT family were similar. hRFT-mediated uptake of [ 3H]riboflavin was inhibited by some riboflavin analogs, but not D-ribose, organic ions, or other vitamins. The newly isolated hRFT3 may play an important role in brain riboflavin homeostasis. Its amino acid sequence and functional characteristics are similar to those of hRFT1, but not hRFT2. © 2010 American Society for Nutrition.

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Impact of cyclin B2 and cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats

Kumiko Nishihara, Satohiro Masuda, Shunsaku Nakagawa, Atsushi Yonezawa, Takaharu Ichimura, Joseph V. Bonventre, Ken-Ichi Inui

American Journal of Physiology - Renal Physiology （4） 298 （ 4 ） F923 - F934 2010年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0363-6127

To clarify the specific molecular events of progressive tubular damage in chronic renal failure (CRF), we conducted microarray analyses using isolated proximal tubules from subtotally nephrectomized (Nx) rats as a model of CRF. Our results clearly demonstrated time-dependent changes in gene expression profiles localized to proximal tubules. The expression of mitosis-specific genes Cyclin B2 and Cell division cycle 2 (Cdc2) was significantly and selectively increased in the proximal tubules during the compensated period but decreased to basal level in the end-stage period. Administration of everolimus, a potent inhibitor of mammalian target of rapamycin, markedly reduced compensatory hypertrophy and hyperplasia of epithelial cells, which was accompanied by complete abolishment of the expression of Cyclin B2 and Cdc2 enhancement
renal function was then severely decreased. Treatment with the Cdc2 inhibitor 2-cyanoethyl alsterpaullone clearly decreased epithelial cell hyperplasia, based on staining of phosphorylated histone H3 and Ki-67, while hypertrophy was not inhibited. In conclusion, we have demonstrated roles of Cyclin B2 and Cdc2 in the epithelial hyperplasia in response to Nx. These results advance the knowledge of the contribution of cell cycle regulators, especially M phase, in pathophysiology of tubular restoration and/or degeneration, and these two molecules are suggested to be a marker for the proliferation of proximal tubular cells in CRF. Copyright © 2010 the American Physiological Society.

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Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients

Toyama K., Yonezawa A., Tsuda M., Masuda S., Yano I., Terada T., Osawa R., Katsura T., Hosokawa M., Fujimoto S., Inagaki N., Inui K.

Pharmacogenetics and Genomics （Pharmacogenetics and Genomics） 20 （ 2 ） 135 - 138 2010年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17446872

Multidrug and toxin extrusions (MATE1/SLC47A1 and MATE2-K/SLC47A2) play important roles in the renal excretion of metformin. We have previously identified the nonsynonymous MATE variants with functional defects at low allelic frequencies. The purpose of this study was to evaluate the effects of heterozygous MATE variants on the disposition of metformin in mice and humans. Pharmacokinetic parameters of metformin in Mate1(±) heterozygous mice were comparable with those in Mate1(+/+) wild-type mice. Among 48 Japanese diabetic patients, seven patients carried heterozygous MATE variant and no patient carried homozygous MATE variant. There was no significant difference in oral clearance of metformin with or without heterozygous MATE variants. In addition, creatinine clearance, but not heterozygous MATE variants, significantly improved the model fit of metformin clearance by statistical analysis using the nonlinear mixed-effects modeling program. In conclusion, heterozygous MATE variants could not influence the disposition of metformin in diabetic patients. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients

Hosohata K., Masuda S., Yonezawa A., Katsura T., Oike F., Ogura Y., Takada Y., Egawa H., Uemoto S., Inui K.

Pharmaceutical Research （Pharmaceutical Research） 26 （ 7 ） 1590 - 1595 2009年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07248741

Purpose: This study investigated whether haplotypes in the multidrug resistance 1 (MDR1) gene had effects on mRNA expression levels of MDR1 and cytochrome P450 (CYP) 3A4, and on the pharmacokinetics of tacrolimus in living-donor liver transplant (LDLT) patients, considering the gender difference. Methods: Haplotype analysis of MDR1 with G2677T/A and C3435T was performed in 63 de novo Japanese LDLT patients (17 to 55 years; 44.4% women). The expression levels of MDR1 and CYP3A4 mRNAs in jejunal biopsy specimens were quantified by real-time PCR. Results: Intestinal CYP3A4 mRNA expression levels (amol/μg total RNA) showed significantly higher values in women carrying the 2677TT-3435TT haplotype (median, 10.7; range, 5.92-15.2) than those with 2677GG-3435CC (3.03; range 1.38-4.68) and 2677GT-3435CT (median, 4.31; range, 0.07-9.42) (P∈=∈0.022), but not in men (P∈=∈0.81). However, MDR1 haplotype did not influence mRNA expression levels of MDR1 nor the concentration/dose ratio [(ng/mL)/(mg/day)] of oral tacrolimus for the postoperative 7 days, irrespective of gender. Conclusion: MDR1 haplotype may have a minor association with the tacrolimus pharmacokinetics after LDLT, but could be a good predictor of the inter-individual variation of intestinal expression of CYP3A4 in women. © 2009 Springer Science+Business Media, LLC.

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Risk factors for recurrence of primary sclerosing cholangitis after living donor liver transplantation: A single center experience

Egawa H., Taira K., Teramukai S., Haga H., Ueda Y., Yonezawa A., Masuda S., Tsuji H., Ashihara E., Takada Y., Uemoto S.

Digestive Diseases and Sciences （Digestive Diseases and Sciences） 54 （ 6 ） 1347 - 1354 2009年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01632116

We retrospectively reviewed our 10-year experience with living donor liver transplantation (LDLT) in 30 consecutive patients with end-stage primary sclerosing cholangitis (PSC) to determine long-term patient and graft survival and risk factors for recurrence of PSC. For strict diagnosis of recurrence, patients with hepatic artery thrombosis (n = 2), ABO blood type incompatible transplantation (n = 3), and postoperative survival shorter than 1 year (n = 5) were excluded from the study, leaving 20 patients for analysis. Recurrence was diagnosed in 11 patients 26-71 months after transplantation. Multivariate analysis showed that cytomegalovirus diseases within 3 months after transplantation and related donors were independent risk factors for recurrence. When the effects on recurrence were compared among donor-recipient relationships, there were significant differences, especially between nonrelated donors and parents. Multivariate analysis showed that age was an independent risk factor for time to graft loss. Cytomegalovirus prophylaxis and avoidance of related donors are important in reducing PSC recurrence, although this is a preliminary report with limitations due to the small number of patients. LDLT for young patients with PSC using grafts from their parents might have to be avoided where deceased donor liver transplantation is available. © 2009 Springer Science+Business Media, LLC.

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Absence of influence of concomitant administration of rabeprazole on the pharmacokinetics of tacrolimus in adult living-donor liver transplant patients: A case-control study

Hosohata K., Masuda S., Yonezawa A., Sugimoto M., Takada Y., Kaido T., Ogura Y., Oike F., Shinji U., Inui K.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 24 （ 5 ） 458 - 463 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

This study assesses the effects of rabeprazole on the pharmacokinetics of tacrolimus, considering the cytochrome P450 (CYP) 2C19 and CYP3A5 genotypes of living-donor liver transplant patients (native intestine) and their corresponding donors (graft liver). We examined the concentration/dose ratio of tacrolimus in transplant patients treated with (n=17) or without (n=38) rabeprazole at 10 mg/day on postoperative days 22-28. A stratified analysis revealed no significant differences between the control and rabeprazole groups in the median (range) concentration/dose ratio of tacrolimus [(ng/mL)/(mg/day)] for CYP2C19 extensive/intermediate metabolizers [2.71 (1.00-6.15) versus 2.55 (0.96-9.25); P=0.85] and for poor metabolizers [4.92 (2.44-7.00) versus 3.82 (2.00-7.31); P=0.68], respectively. Even based on the classification of CYP2C19 genotypes of donors, no significant difference in the concentration/dose ratio of tacrolimus was found for the two groups (CYP2C19 extensive/intermediate metabolizers, P=0.52; poor metabolizers, P=0.51). The same was observed for CYP3A5*1 carriers (P=0.97 for native intestine; P= 0.87 for graft liver) and CYP3A5*3/*3 carriers (P=0.89 for native intestine; P=0.56 for graft liver). These findings suggest a safer dosing and monitoring of tacrolimus coadministered with rabeprazole early on after liver transplantation regardless of the CYP2C19 and CYP3A5 genotypes of transplant patients and their donors.

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Significance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer

Yokoo S., Masuda S., Yonezawa A., Terada T., Katsura T., Inui K.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 36 （ 11 ） 2299 - 2306 2008年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

The effect of oxaliplatin against colorectal cancer is superior to that of cisplatin, but the molecular mechanism(s) involved is not clear. We found previously that oxaliplatin, but not cisplatin, was transported by human (h) and rat organic cation transporter 3 (OCT3)/SLC22A3. In the present study, we examined whether hOCT3 was significantly involved in the oxaliplatin-induced cytotoxicity and accumulation of platinum in colorectal cancer. The level of hOCT3 mRNA in the colon was 9.7-fold higher in cancerous than in normal tissues in six Japanese patients (P = 0.0247). In human colorectal cancer-derived cell lines, the mRNA of hOCT3 was highly expressed compared with that of other organic cation transporters. The release of lactate dehydrogenase (LDH) and accumulation of platinum with oxaliplatin treatment were increased in SW480 cells transfected with hOCT3 cDNA compared with empty vector-transfected cells. T84 and SW837 cells, with high levels of hOCT3, released more LDH and accumulated more platinum after oxaliplatin treatment than low hOCT3-expressing cells such as SW480, HCT116, HT29, and Lovo. However, the amount of platinum accumulated after cisplatin treatment did not differ among these six cell lines. The levels of hOCT3 expression in colon and rectum were also higher in cancerous than in normal tissues in Caucasian patients as determined by dot blotting. In conclusion, the hOCT3-mediated uptake of oxaliplatin into the cancers was suggested to be important for its cytotoxicity, and hOCT3 expression may be a marker for cancer chemotherapy including oxaliplatin. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

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