TICBase: Integrated Resource for Data on Drug and Environmental Chemical Interactions with Mammalian Drug Transporters

Abstract

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.

Figure 1

Drug transporter localization in four representative biological barriers in human. Shown are apical and basolateral membrane localization of all ABC and SLC transporters listed in the database for (a) liver, (b) kidneys, (c) brain, and (d) small intestine (adapted from ref. 16). The anticipated direction of substrate and co-substrate flow are marked with arrows. Tight junctions are displayed as a group of three black bars in the indicated cell type. Newly added human, rodent, and monkey transporters are highlighted in green.

Figure 2

Chemical structures of the most potent inhibitory TICs in the database with IC₅₀ values below 1 μM. Shown are the two ionic liquids (1-hexylpyridinium chloride and N-butyl- N-methylpyrrolidinium chloride) which are potent inhibitors of SLC22A2 (OCT2), SLC22A3 (OCT3), SLC47A1 (MATE1), and SLC47A2 (MATE2-K), the antiseptic Chlorhexidine, which is a potent inhibitor of SLC22A2 (OCT2), and the brominated flame retardant Tetrabromobisphenol A (TBBPA) which potently inhibits two anion transporters SLC22A8 (OAT3) and SLCO1B1 (OATP1B1; Table 2). IC₅₀, half-maximal inhibitory concentration.