Sook Wah Yee

Environmental health science seeks to predict how environmental toxins, chemical toxicants, and prescription drugs accumulate and interact within the body. Xenobiotic transporters of the ATP‐binding cassette (ABC) and solute carrier (SLC) superfamilies are major determinants of the uptake and disposition of xenobiotics across the kingdoms of life. The goal of this study was to integrate drug and environmental chemical interactions of mammalian ABC and SLC proteins in a centralized, integrative database. We built upon an existing publicly accessible platform—the “TransPortal”—which was updated with novel data and searchable features on transporter‐interfering chemicals from manually curated literature data. The integrated resource TransPortal‐TICBase ( https://transportal.compbio.ucsf.edu ) now contains information on 46 different mammalian xenobiotic transporters of the ABC‐ and SLC‐type superfamilies, including 13 newly added rodent and 2 additional human drug transporters, 126 clinical drug–drug interactions, and a more than quadrupled expansion of the initial in vitro chemical interaction data from 1,402 to 6,296 total interactions. Based on our updated database, environmental interference with major human and rodent drug transporters occurs across the ABC‐ and SLC‐type superfamilies, with kinetics indicating that some chemicals, such as the ionic liquid 1‐hexylpyridinium chloride and the antiseptic chlorhexidine, can act as strong inhibitors with potencies similar or even higher than pharmacological model inhibitors. The new integrated web portal serves as a central repository of current and emerging data for interactions of prescription drugs and environmental chemicals with human drug transporters. This archive has important implications for predicting adverse drug–drug and drug‐environmental chemical interactions and can serve as a reference website for the broader scientific community of clinicians and researchers.

The Thiamine Transporter 2 (THTR2) encoded by SLC19A3 plays an ill-defined role in the maintenance of tissue thiamine, thiamine monophosphate, and thiamine diphosphate (TDP) levels. To evaluate the impact of THTR2 on tissue thiamine status and metabolism, we expressed the human SLC19A3 transgene in the intestine of total body Slc19a3 knockout (KO) mice. Male and female wildtype (WT) and transgenic (TG) mice were fed either 17 mg/kg (1×) or 85 mg/kg (5×) thiamine hydrochloride diet, while KOs were only fed the 5× diet. Thiamine vitamers in plasma, red blood cells, duodenum, brain, liver, kidney, heart, and adipose tissue were measured. Untargeted metabolomics were performed on the brain tissues of groups with equivalent plasma thiamine. KO mice had ~two- and ~three-fold lower plasma and brain thiamine levels than WT on the 5× diet. Circulating vitamers were sensitive to diet and equivalent in TG and WT mice. However, TG had 60% lower thiamine but normal brain TDP levels regardless of diet, with subtle differences in the heart and liver. The loss of THTR2 reduced levels of nucleic acid and amino acid derivatives in the brain. Therefore, mutation or inhibition of THTR2 may alter the brain metabolome and reduce the thiamine reservoir for TDP biosynthesis.

Trimethoprim is predicted to inhibit several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR‐2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real‐world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co‐administration ( P value = 0.031). Similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real‐world data further supported this finding, showing an association between trimethoprim use and higher levels of triglycerides, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition ( P values: 2.2 × 10 −16 , 5.75 × 10 −7 , and 5.82 × 10 −7 , respectively). These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, consistent with inhibition of renal organic cation transporters. This inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug‐nutrient interactions involving transporters, in addition to transporters' established role in drug–drug interactions.