Endocrinology, Vol 130, 1211-1216, Copyright © 1992 by Endocrine Society

ARTICLES

Benzodiazepines inhibit temperature-dependent L-[125I]triiodothyronine accumulation into human liver, human neuroblast, and rat pituitary cell lines

L Kragie and D Doyle
Department of Biological Sciences, Faculty of Natural Sciences and Mathematics, State University of New York, Buffalo 14260.

L-T3 (T3) accumulates into cells in a temperature-dependent saturable manner through a purported iodothyronine membrane carrier protein. We report energy-dependent uptake of picomolar [125I]T3 into differentiated cell lines derived from human liver, human neuroblast, and rat pituitary malignancies. Furthermore, this cellular uptake is inhibited by classical and nonclassical benzodiazepine-type drugs (BZs); the apparent half-maximal inhibitory concentrations range from 50 nM to 50 microM, varying with drug and cell type. The site of this T3-BZ interaction was explored with cross-competitive radioligand binding to rat liver cell fractions. No interaction was seen in experiments cross-competing unlabeled T3 (10(-9)-10(-5) M) against [3H]Ro5 4864, a peripheral BZ receptor ligand, for binding sites in a crude rat liver mitochondrial fraction. As well, lormetazepam and triazolam, BZs that potently inhibit cellular uptake of [125I]T3, have no effect on [125I]T3 binding to rat liver nuclear sites. Studies of [3H]diazepam and [3H]Ro5 4864 show very little temperature-dependent uptake into HepG2 cells (less than 0.5% over 90 min) and no effect from coincubation of unlabeled T3 (1 microM). Thus, the possibility that BZs are substrates for the T3 carrier protein and are causing the reduced cellular hormonal accumulation via competitive uptake and dilution of the radiolabeled cellular T3 is unlikely. In summary, 1) drugs from the BZ class inhibit high affinity temperature-dependent cellular accumulation of thyroid hormone into cell lines from rat and human species; 2) the site of action of BZ inhibition does not involve direct antagonism of the T3 nuclear receptor, nor is it likely that the peripheral BZ receptor is the iodothyronine carrier. BZs could be interacting with the purported iodothyronine carrier protein itself to block uptake.

This article has been cited by other articles:

				G. Hennemann, R. Docter, E. C. H. Friesema, M. de Jong, E. P. Krenning, and T. J. Visser Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability Endocr. Rev., August 1, 2001; 22(4): 451 - 476. [Abstract] [Full Text] [PDF]

				T. Abe, M. Kakyo, T. Tokui, R. Nakagomi, T. Nishio, D. Nakai, H. Nomura, M. Unno, M. Suzuki, T. Naitoh, et al. Identification of a Novel Gene Family Encoding Human Liver-specific Organic Anion Transporter LST-1 J. Biol. Chem., June 11, 1999; 274(24): 17159 - 17163. [Abstract] [Full Text] [PDF]

				R. C.J. Ribeiro, R. R. Cavalieri, N. Lomri, C. M. Rahmaoui, J. D. Baxter, and B. F. Scharschmidt Thyroid Hormone Export Regulates Cellular Hormone Content and Response J. Biol. Chem., July 19, 1996; 271(29): 17147 - 17151. [Abstract] [Full Text] [PDF]