The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2

AAPS J. 2021 Mar 1;23(2):35. doi: 10.1208/s12248-021-00562-4.


A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.

Keywords: THTR1; drug nutrient interactions; drug-induced megaloblastic anemia; thiamine diphosphate; vitamin b1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anemia, Megaloblastic / blood
  • Anemia, Megaloblastic / chemically induced
  • Anemia, Megaloblastic / genetics*
  • Cell Membrane / metabolism
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / chemically induced
  • Diabetes Mellitus / genetics*
  • Drug Interactions
  • Erythromycin / adverse effects*
  • Erythromycin / pharmacokinetics
  • Female
  • Genetic Variation
  • HEK293 Cells
  • Hearing Loss, Sensorineural / blood
  • Hearing Loss, Sensorineural / chemically induced
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Loss of Function Mutation
  • Male
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Thiamine Deficiency / blood
  • Thiamine Deficiency / chemically induced
  • Thiamine Deficiency / congenital*
  • Thiamine Deficiency / genetics
  • Thiamine Pyrophosphate / antagonists & inhibitors*
  • Thiamine Pyrophosphate / blood
  • Thiamine Pyrophosphate / metabolism


  • Membrane Transport Proteins
  • SLC19A2 protein, human
  • Erythromycin
  • Thiamine Pyrophosphate

Supplementary concepts

  • Thiamine responsive megaloblastic anemia syndrome