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

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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.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

FILI:

Flutamide-induced liver injury

FLU-1:

4-Nitro-3-(trifluoromethyl)phenylamine

MATE1:

Multidrug and toxin extrusion protein 1

SLC47A1:

Solute carrier family 47 (multidrug and toxin extrusion), member 1

SNP:

Single nucleotide polymorphism

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Acknowledgments

We are grateful to Mrs. Hisae Shiokawa and Dr. Hidetoshi Tsuda for technical assistance and to Dr. Kenji Komatsu, Dr. Takeshi Koshimizu, Dr. Shinsuke Natsui, Dr. Kazumi Suzuki, Dr. Masayuki Yuzawa, and Dr. Minoru Kobayashi for collecting patients’ data. We also thank all the participants for their cooperation. This work was supported by a grant from the Ministry of Health, Labor, and Welfare of Japan (H20-BIO-G-003).

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

    Authors and Affiliations

    1. Department of Urology, Jichi Medical University, Shimotsuke, Japan

      Kazuhiko Nakano, Shinsuke Kurokawa & Tatsuo Morita

    2. Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan

      Hitoshi Ando, Keiko Hosohata, Kentarou Ushijima & Akio Fujimura

    3. Division of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, Japan

      Makoto Takada & Masato Tateishi

    4. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto University, Kyoto, Japan

      Atsushi Yonezawa, Satohiro Masuda & Kazuo Matsubara

    5. Kyoto Pharmaceutical University, Kyoto, Japan

      Ken-ichi Inui

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    1. Kazuhiko Nakano
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    Correspondence to Akio Fujimura.

    Additional information

    Kazuhiko Nakano and Hitoshi Ando have contributed equally to this study.

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    Nakano, K., Ando, H., Kurokawa, S. et al. 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 Chemother Pharmacol 75, 1191–1197 (2015). https://doi.org/10.1007/s00280-015-2743-6

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    • DOI: https://doi.org/10.1007/s00280-015-2743-6

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