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J. Biol. Chem., Vol. 278, Issue 23, 20695-20699, June 6, 2003

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The Human Organic Anion Transport Protein SLC21A6 Is Not Sufficient for Bilirubin Transport^*

Pijun Wang , Richard B. Kim , J. Roy Chowdhury  and Allan W. Wolkoff  ¶

From the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461 and Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

A recent study (Cui, Y., Konig, J., Leier, I., Buchholz, U., and Keppler, D. (2001) J. Biol. Chem. 276, 9626–9630) suggests that human OATP2 (SLC21A6), also known as OATP-C and LST1, mediates hepatic bilirubin transport. Because of methodologic concerns, this study was designed to examine this issue using a bilirubin transport assay that was validated in overnight cultured rat hepatocytes. These studies showed that cultured rat hepatocytes transported bilirubin with kinetics virtually identical to the transport of sulfobromophthalein. This assay was then used to quantify bilirubin transport by HeLa cells that had been stably transfected with OATP2 under regulation of a metallothionein promoter. Immunoblot analysis revealed abundant expression of OATP2 after incubation of cells for 48 h in zinc, whereas uninduced cells had no expression of this protein. In OATP2-expressing (zinc-induced) HeLa cells at 37 °C, the uptake of [³⁵S]sulfobromophthalein was substantial (51.6 ± 16.5 pmol/15 min/mg protein, n = 5) with little cell-associated ligand in non-expressing (uninduced) cells (0.54 ± 0.16 pmol/15 min/mg protein, n = 5, p < 0.002). In contrast, there was no difference (p > 0.2) in cell-associated [³H]bilirubin in induced (OATP2-expressing) as compared with uninduced cells (11.25 ± 3.02 pmol/15 min/mg protein versus 9.15 ± 1.68 pmol/min/mg protein, respectively, n = 5) We obtained similar results in OATP2-transfected HEK293 cells that were used in the original report. The existence of a bilirubin transporter has been an important field of investigation for many years. Although the current study indicates that a role for OATP2 in hepatocyte bilirubin transport is unlikely, it provides new and sensitive tools that can be adapted to examine the function of putative bilirubin transporters in the future.

Received for publication, January 31, 2003 , and in revised form, March 18, 2003.

^* This work was supported by in part by National Institutes of Health Grants DK23026 (to A. W. W.), GM54724 (to R. B. K.), and DK46057 (to J. R. C.) and a grant from Bristol-Myers Squibb Co. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Marion Bessin Liver Research Center, 625 Ullmann Bldg., Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-3798; Fax: 718-430-8975; E-mail: wolkoff{at}aecom.yu.edu.

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