Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury

Kazuhiko Nakano, Hitoshi Ando, Shinsuke Kurokawa, Keiko Hosohata, Kentarou Ushijima, Makoto Takada, Masato Tateishi, Atsushi Yonezawa, Satohiro Masuda, Kazuo Matsubara, Ken Ichi Inui, Tatsuo Morita, Akio Fujimura

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. Methods: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Results: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. Conclusions: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.

Original languageEnglish
Pages (from-to)1191-1197
Number of pages7
JournalCancer chemotherapy and pharmacology
Volume75
Issue number6
DOIs
Publication statusPublished - Jun 26 2015

Fingerprint

Flutamide
Liver
Extrusion
Blood Cells
Blood
Cells
Messenger RNA
Wounds and Injuries
Proteins
Biomarkers
Microarrays
Prostatic Neoplasms
Aniline Compounds
Genes
Pharmaceutical Preparations
Pharmacokinetics
Microarray Analysis
Metabolites
Aspartate Aminotransferases
Serum

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury. / Nakano, Kazuhiko; Ando, Hitoshi; Kurokawa, Shinsuke; Hosohata, Keiko; Ushijima, Kentarou; Takada, Makoto; Tateishi, Masato; Yonezawa, Atsushi; Masuda, Satohiro; Matsubara, Kazuo; Inui, Ken Ichi; Morita, Tatsuo; Fujimura, Akio.

In: Cancer chemotherapy and pharmacology, Vol. 75, No. 6, 26.06.2015, p. 1191-1197.

Research output: Contribution to journalArticle

Nakano, K, Ando, H, Kurokawa, S, Hosohata, K, Ushijima, K, Takada, M, Tateishi, M, Yonezawa, A, Masuda, S, Matsubara, K, Inui, KI, Morita, T & Fujimura, A 2015, 'Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury', Cancer chemotherapy and pharmacology, vol. 75, no. 6, pp. 1191-1197. https://doi.org/10.1007/s00280-015-2743-6
Nakano, Kazuhiko ; Ando, Hitoshi ; Kurokawa, Shinsuke ; Hosohata, Keiko ; Ushijima, Kentarou ; Takada, Makoto ; Tateishi, Masato ; Yonezawa, Atsushi ; Masuda, Satohiro ; Matsubara, Kazuo ; Inui, Ken Ichi ; Morita, Tatsuo ; Fujimura, Akio. / Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury. In: Cancer chemotherapy and pharmacology. 2015 ; Vol. 75, No. 6. pp. 1191-1197.
@article{a813ef302f874e4ea5b4746179c82611,
title = "Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury",
abstract = "Purpose: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. Methods: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Results: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. Conclusions: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.",
author = "Kazuhiko Nakano and Hitoshi Ando and Shinsuke Kurokawa and Keiko Hosohata and Kentarou Ushijima and Makoto Takada and Masato Tateishi and Atsushi Yonezawa and Satohiro Masuda and Kazuo Matsubara and Inui, {Ken Ichi} and Tatsuo Morita and Akio Fujimura",
year = "2015",
month = "6",
day = "26",
doi = "10.1007/s00280-015-2743-6",
language = "English",
volume = "75",
pages = "1191--1197",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury

AU - Nakano, Kazuhiko

AU - Ando, Hitoshi

AU - Kurokawa, Shinsuke

AU - Hosohata, Keiko

AU - Ushijima, Kentarou

AU - Takada, Makoto

AU - Tateishi, Masato

AU - Yonezawa, Atsushi

AU - Masuda, Satohiro

AU - Matsubara, Kazuo

AU - Inui, Ken Ichi

AU - Morita, Tatsuo

AU - Fujimura, Akio

PY - 2015/6/26

Y1 - 2015/6/26

N2 - Purpose: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. Methods: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Results: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. Conclusions: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.

AB - Purpose: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. Methods: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Results: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. Conclusions: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.

UR - http://www.scopus.com/inward/record.url?scp=84929712391&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929712391&partnerID=8YFLogxK

U2 - 10.1007/s00280-015-2743-6

DO - 10.1007/s00280-015-2743-6

M3 - Article

C2 - 25862351

AN - SCOPUS:84929712391

VL - 75

SP - 1191

EP - 1197

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 6

ER -