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Takeshita A.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Igarashi-migitaka J.,St. Marianna University School of Medicine | Nishiyama K.,Teikyo University | Takahashi H.,Teikyo University | And 2 more authors.
Toxicological Sciences | Year: 2011

Steroid and xenobiotic receptor (SXR) is activated by endogenous and exogenous chemicals including steroids, bile acids, and prescription drugs. SXR is highly expressed in the liver and intestine, where it regulates cytochrome P450 3A4 (CYP3A4), which in turn controls xenobiotic and endogenous steroid hormone metabolism. However, it is unclear whether Food and Drug Administration (FDA)-approved plasticizers exert such activity. In the present study, we evaluated the effects of FDA-approved plasticizers on SXR-mediated transcription in vitro by luciferase reporter, SXR-coactivator interaction, quantitative real-time PCR analysis of CYP3A4 expression, CYP3A4 enzyme activity assays, and SXR knockdown. Rats, treated with gavage and intraperitoneal injection of compounds, were examined for CYP3A1 expression in vivo. We found that four of eight FDA-approved plasticizers increased SXR-mediated transcription. In particular, acetyl tributyl citrate (ATBC), an industrial plasticizer widely used in products such as food wrap, vinyl toys, and pharmaceutical excipients, strongly activated human and rat SXR. ATBC increased CYP3A4 messenger RNA (mRNA) levels and enzyme activity in the human intestinal cells but not in human liver cells. Similarly, CYP3A1 mRNA levels were increased in the intestine but not the liver of ATBC-treated rats. These in vitro and in vivo results suggest that ATBC specifically induces CYP3A in the intestine by activating SXR. We suggest that ATBC-containing products be used cautiously because they may alter metabolism of endogenous steroid hormones and prescription drugs. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. Source


Takeshita A.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Igarashi-Migitaka J.,St. Marianna University School of Medicine | Koibuchi N.,Gunma University | Takeuchi Y.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research
Journal of Endocrinology | Year: 2013

Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. Mitotane alone or in combination with other cytotoxic drugs is a common therapeutic option for ACC. In addition to its adrenolytic function, mitotane has been known for decades to increase the metabolic clearance of glucocorticoids. It was recently shown that the tyrosine kinase inhibitor sunitinib is also rapidly metabolized in patients treated with mitotane, indicating that mitotane engages in clinically relevant drug interactions. Although the precise mechanism of these interactions is not well understood, cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic receptor (SXR (NR1I2)) is one of the key transcriptional regulators of CYP3A4 gene expression in the liver and intestine. A variety of xenobiotics bind to SXR and stimulate transcription of xenobiotic-response elements (XREs) located in the CYP3A4 gene promoter. In this study, we evaluated the effects of mitotane on SXR-mediated transcription in vitro by luciferase reporter analysis, SXR-steroid receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis of CYP3A4 expression, SXR knockdown, and CYP3A4 enzyme activity assays using human hepatocyte-derived cells. We found that mitotane activated SXR-mediated transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain of SXR. Mitotane increased CYP3A4 mRNA levels, which was attenuated by SXR knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity.We conclude that mitotane can induce CYP3A4 gene expression and suggest that mitotane is used cautiously due to its drug-drug interactions. © 2013 Society for Endocrinology. Source


Tabata M.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Ikeda M.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Urakami S.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Takahashi S.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | And 3 more authors.
Japanese Journal of Clinical Oncology | Year: 2015

Objective: To evaluate the effectiveness of adjuvant chemotherapy in patients with pathological Stage T3 bladder cancer who had undergone radical cystectomy, and to determine the prognostic survival factors for adjuvant chemotherapy treatment. Methods: From January 1990 to October 2013, 202 patients underwent radical cystectomy and pelvic lymphadenectomy. Among them, 65 patients with non-organ-confined disease (pT3, N0-3, M0) diagnosed were investigated in this study. Thirty-one patients (48%) were treated with adjuvant chemotherapy and the remaining 34 patients (52%) were not. Results: Median age of all patients was 66 years, and median follow-up was 26.1 months. For all pT3 patients, overall survival and disease-free survival times were similar in the adjuvant chemotherapy and non-adjuvant chemotherapy groups. However, in the pT3b subgroup, median overall survival (47.0 vs. 10.6 months) and median disease-free survival (35.5 vs. 5.3 months) times were significantly prolonged for those who underwent adjuvant chemotherapy (P = 0.009 and 0.025). In patients with pathological lymph node metastatic (pN+), median overall survival (30.1 vs. 6.4 months) and median disease-free survival (15.7 vs. 3.5 months) times were significantly prolonged in the adjuvant chemotherapy group (P = 0.016 and 0.027). In addition, according to multivariate analysis in pT3b and/or pN+ subgroup patients, adjuvant chemotherapy status was an independent predictive factor for overall survival and disease-free survival. Conclusion: Adjuvant chemotherapy did not significantly improve overall survival and disease-free survival when compared with all patients with pT3 who had received radical cystectomy in the non-adjuvant chemotherapy group. However, in the pT3b and pN+ subgroup, adjuvant chemotherapy demonstrated statistically significant benefits regarding overall survival and disease-free survival. Although these results could not support adjuvant chemotherapy use for all pT3 patients, the pT3b substage and/or pN+ may help identify patients with pT3 who could benefit from adjuvant chemotherapy. © 2015 The Author. Published by Oxford University Press. Source


Akuta N.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Suzuki F.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Sezaki H.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Hosaka T.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | And 6 more authors.
Journal of Medical Virology | Year: 2015

The present study was designed to assess the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time in virological non-responders (patients with positive HCV-RNA during and at end of treatment). The study enrolled 136 patients infected with HCV genotype 1b who received 12-week simeprevir-PEG-IFN-ribavirin therapy, and data of 87 patients were available for analysis. Twelve patients (14%) were considered virological non-responders, including 9 (75%) who showed absolute no-response (HCV RNA: ≥3.0 log IU/ml at 12 weeks after start of therapy). Multivariate analysis of these patients identified lack of response to prior treatment, use of low ribavirin dose, and old age as independent and significant determinants of virological non-response. Using ultra-deep sequencing, de novo variants of D168 were detected in all of 9 absolute non-responders. The majority of these variants emerged within 5 weeks of triple therapy. In comparison, de novo variants of Q80 were detected in only 3 of 9 absolute non-responders and emerged at 6-12 weeks. Variants of Q80 detected at baseline increased during the course of treatment in 5 of 9 absolute non-responders, while no such increase was noted in variants of R155 and/or A156 detected at baseline during the 12-week course. De novo variants of R155 and/or A156 were not detected in this study. The results demonstrated the emergence of simeprevir-resistant variants during the early stage of triple therapy. © 2015 Wiley Periodicals, Inc. Source


Akuta N.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Suzuki F.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Sezaki H.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | Suzuki Y.,Toranomon Hospital and Okinaka Memorial Institute for Medical Research | And 6 more authors.
Journal of Medical Virology | Year: 2014

Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants. © 2014 Wiley Periodicals, Inc. Source

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