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Thyroid Hormone Export in Rat FRTL-5 Thyroid Cells and Mouse NIH-3T3 Cells Is Carrier-Mediated, Verapamil-Sensitive, and Stereospecific¹

Nuclear Medicine Research Laboratory, Veterans Administration Medical Center (R.R.C.), San Francisco, California; the Department of Pharmaceutical Sciences, University of Brasilia (L.A.S., R.C.J.R.), Brasilia, DF Brazil; University of California (S.W.P.), Davis, California 95817; and the Metabolic Research Unit (J.D.B.), Gastroenterology Division (B.F.S., N.L.), and Liver Center (R.R.C., B.F.S., N.L.), Department of Medicine, University of California, San Francisco, California 94143-0538

Address all correspondence and requests for reprints to: Dr. Noureddine Lomri, Gastroenterology Division, University of California, 513 Parnassus Avenue, S-357, P.O. Box 0538, San Francisco, California 94143. E-mail: nlomri{at}itsa.ucsf.edu

Export of L-T₃ out of the cell is one factor governing the cellular T₃ content and response. We previously observed in liver-derived cells that T₃ export was inhibited by verapamil, suggesting that it is due to either ATP-binding cassette/multidrug resistance (MDR1/mdr1b) or multidrug resistance-related (MRP1/mrp1) proteins. To test this hypothesis we measured T₃ export in FRTL-5, NIH-3T3, and rat hepatoma (HTC) cells that varied in expression of these proteins. FRTL-5 and NIH-3T3 cells were found to contain a T₃ efflux mechanism that is verapamil inhibitable, saturable, and stereospecific. By contrast, T₃ efflux in HTC cells was slow and unaffected by verapamil. Neither FRTL-5 nor NIH-3T3 cells express mdr1b, but all three cell types express mrp1, as assessed by immunoblotting. Overexpression of MDR1 in NIH-3T3 cells did not enhance verapamil-inhibitable T₃ efflux. Photoaffinity labeling of FRTL-5 and NIH-3T3 cells with [¹²⁵I]L-T₃ revealed a labeled 90- to 100-kDa protein that was not present in HTC cells. Verapamil and excess nonradioactive L-T₃, but not D-T₃, inhibited labeling of this protein. The lack of correlation between T₃ efflux and MDR1 and mrp1 expression and the finding of a photoaffinity-labeled putative transport protein smaller than MDR1 or mrp1 protein (170 kDa) suggest that a novel protein is involved in the transport of T₃ out of cells.

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