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Hepatocyte Nuclear Factor 1 Alpha is a Factor Responsible for the Interindividual Variation of OATP1B1 mRNA Levels in Adult Japanese Livers

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Abstract

Purpose

The aim of the present study was to clarify the factors responsible for interindividual variability of organic anion transporting polypeptide (OATP, gene symbol SLCO) 1B1 mRNA expression level in the human liver.

Materials and Methods

OATP1B1 mRNA expression levels were determined by real-time PCR in 31 human liver samples. The results were analyzed in relation to a single nucleotide polymorphism (−11187G>A) located in the promoter region and levels of hepatocyte nuclear factor (HNF) 1α mRNA.

Results

There was a 4.9-fold interindividual variability of OATP1B1 mRNA expression level in the livers analyzed, which was not associated with −11187G>A polymorphism. Accordingly, the −11187G>A polymorphism did not alter the SLCO1B1 gene promoter activity in luciferase assays. On the other hand, OATP1B1 mRNA levels showed a significant correlation with HNF1α mRNA levels (r = 0.83, P < 0.0001). This correlation was consistent with the results of luciferase assays and chromatin immunoprecipitation assays showing functional interaction between HNF1α and SLCO1B1 gene promoter.

Conclusions

Our results suggest that HNF1α is an essential regulator of OATP1B1 mRNA expression and thus the level of HNF1α expression is one of the major determinants of interindividual variability in OATP1B1 mRNA expression.

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Abbreviations

HNF:

Hepatocyte nuclear factor

MODY:

Maturity-onset diabetes of the young

OATP:

Organic anion transporting polypeptide

PCR:

Polymerase chain reaction

SLCO:

Solute carrier organic anion transporter

SNP:

Single nucleotide polymorphism

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Acknowledgements

We would like to thank Dr. Masayoshi Tani, Dr. Hironobu Minami, Dr. Yasutsuna Sasaki and Dr. Satoshi Suzuki for their cooperation. We thank Dr. Ryuichirou Satoh (Lab. of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo) for providing HNF1α expression plasmid. We would also like to thank Dr. Masakiyo Hosokawa, Dr. Kaori Morimoto, Sasitorn Aueviriyavit, MS and other laboratory members for their technical assistance.

This work was supported by a grant (18890044) from the Ministry of Education, Sciences, Sports and Culture of Japan and by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan (Health and Labor Sciences Research Grants, Risk Analysis Research on Food and Pharmaceuticals).

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Authors and Affiliations

  1. Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan

    Tomomi Furihata, Tomomi Satoh, Naoko Yamamoto, Kaoru Kobayashi & Kan Chiba

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  1. Tomomi Furihata
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  2. Tomomi Satoh
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  3. Naoko Yamamoto
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  4. Kaoru Kobayashi
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  5. Kan Chiba
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Correspondence to Tomomi Furihata.

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Tomomi Satoh and Naoko Yamamoto equally contributed to this work.

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Furihata, T., Satoh, T., Yamamoto, N. et al. Hepatocyte Nuclear Factor 1 Alpha is a Factor Responsible for the Interindividual Variation of OATP1B1 mRNA Levels in Adult Japanese Livers. Pharm Res 24, 2327–2332 (2007). https://doi.org/10.1007/s11095-007-9458-2

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  • DOI: https://doi.org/10.1007/s11095-007-9458-2

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