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¹ Conjoint Endocrine Laboratory, Royal Brisbane and Women’s Hospital Research Foundation, Bancroft Centre, Brisbane, Queensland 4029, Australia
² Queensland Health Pathology Service, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
³ Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
⁴ Department of Obstetrics and Gynaecology, University of Queensland, Brisbane, Queensland 4029, Australia

(Requests for offprints should be addressed to R H Mortimer, Royal Brisbane and Women’s Hospital, Base Hospitals, Herston, Queensland 4029, Australia; Email: Robin Mortimer{at}health.qld.gov.au)

Verapamil inhibits tri-iodothyronine (T₃) efflux from several cell types, suggesting the involvement of multidrug resistance-associated (MDR) proteins in T₃ transport. The direct involvement of P-glycoprotein (P-gp) has not, however, been investigated. We compared the transport of ¹²⁵I-T₃ in MDCKII cells that had been transfected with mdr1 cDNA (MDCKII-MDR) versus wild-type MDCKII cells (MDCKII), and examined the effect of conventional (verapamil and nitrendipine) and specific MDR inhibitors (VX 853 and VX 710) on ¹²⁵I-T₃ efflux. We confirmed by Western blotting the enhanced expression of P-gp in MDCKII-MDR cells. The calculated rate of ¹²⁵I-T₃ efflux from MDCKII-MDR cells (around 0.30/min) was increased twofold compared with MDCKII cells (around 0.15/min). Overall, cellular accumulation of ¹²⁵I-T₃ was reduced by 26% in MDCKII-MDR cells compared with MDCKII cells, probably reflecting enhanced export of T₃ from MDCKII-MDR cells rather than reduced cellular uptake, as P-gp typically exports substances from cells. Verapamil lowered the rate of ¹²⁵I-T₃ efflux from both MDCKII and MDCKII-MDR cells by 42% and 66% respectively, while nitrendipine reduced ¹²⁵I-T₃ efflux rate by 36% and 48% respectively, suggesting that both substances inhibited other cellular T₃ transporters in addition to P-gp. The specific MDR inhibitors VX 853 and VX 710 had no effect of ¹²⁵I-T₃ efflux rate from wild-type MDCKII cells but reduced ¹²⁵I-T₃ export in MDCKII-MDR cells by 50% and 53% respectively. These results have provided the first direct evidence that P-gp exports thyroid hormone from cells.

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