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Research ArticleArticle

The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Qi Wang and Marilyn E. Morris
Drug Metabolism and Disposition August 2007, 35 (8) 1393-1399; DOI: https://doi.org/10.1124/dmd.107.014852
Qi Wang
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Marilyn E. Morris
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Abstract

Monocarboxylate transporter 1 (MCT1) is an important determinant of the renal transport of the drug of abuse, γ-hydroxybutyric acid (GHB). The objective of this study was to investigate the role of MCT2 and MCT4, present in tissues including intestine, kidney, skeletal muscle, and brain, in the membrane transport of GHB and the MCT substrate l-lactate. mRNA and protein of MCT2 and MCT4 were expressed in MDA-MB231 cells, as detected by reverse transcription-polymerase chain reaction and Western blot analysis; MCT1 and MCT3 were not detected. The uptake of GHB or l-lactate by MDA-MB231 cells was pH-dependent but not sodium-dependent. The concentration-dependent uptake of GHB was best fitted to a single-transporter model with a diffusional clearance component (Km of 17.6 ± 1.5 mM, Vmax of 50.6 ± 9.0 nmol · mg–1 min–1 and diffusional clearance of 0.20 ± 0.07 μl · mg–1 min–1). On the other hand, the concentration-dependent uptake of l-lactate was best fitted to a two-transporter model (Km of 21 ± 2.5 and 3.0 ± 1.5 mM, and Vmax of 268 ± 72 and 62.9 ± 42.2 nmol · mg–1min–1, respectively). The uptake of GHB and l-lactate was inhibited by MCT inhibitors α-cyano-4-hydroxycinnamate (CHC), phloretin, and p-chloromercuribenzoic acid; CHC inhibited GHB and l-lactate uptake with IC50 values of 1.71 ± 0.39 and 0.71 ± 0.11 mM, respectively. Small interfering RNA treatment to silence MCT2 or MCT4 significantly decreased their protein expression and the uptake of l-lactate and GHB; however, the decrease in GHB uptake with MCT2 inhibition was smaller than that for MCT4. This investigation demonstrated that GHB is a substrate for both MCT2 and MCT4; these transporters may be important in the nonlinear disposition of GHB, as well as influencing its tissue distribution.

Footnotes

  • Financial support was provided by National Institutes of Health Grant DA14988 and a grant from the Western New York Kidney Foundation/Upstate NY Transplantation Service.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.014852.

  • ABBREVIATIONS: GHB, γ-hydroxybutyrate; MCT, monocarboxylate transporter; CHC, α-cyano-4-hydroxycinnamate; pCMB, p-chloromercuribenzoic acid; TEA, tetraethylammonium chloride; RT-PCR, reverse transcription-polymerase chain reaction; siRNA, small interfering RNA; ANOVA, analysis of variance; BBB, blood-brain barrier.

    • Received January 19, 2007.
    • Accepted May 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (8)
Drug Metabolism and Disposition
Vol. 35, Issue 8
1 Aug 2007
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Research ArticleArticle

The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Qi Wang and Marilyn E. Morris
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1393-1399; DOI: https://doi.org/10.1124/dmd.107.014852

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Research ArticleArticle

The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Qi Wang and Marilyn E. Morris
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1393-1399; DOI: https://doi.org/10.1124/dmd.107.014852
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