Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat

Abstract

Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The expression patterns/enrichment of ABC transporter genes in brain microvessels compared to peripheral vessels and tissues are largely uncharacterized. Methods: In this study, the expression patterns of ABC transporter genes in brain microvessels, peripheral tissues (lung, liver and spleen) and lung vessels were investigated using RNA-seq and WesTM analyses in three species: human, mouse and rat. Results: The study demonstrated that ABC drug efflux transporter genes (including ABCB1, ABCG2, ABCC4 and ABCC5) were highly expressed in isolated brain microvessels in all three species studied; the expression of ABCB1, ABCG2, ABCC1, ABCC4 and ABCC5 was generally higher in rodent brain microvessels compared to those of humans. In contrast, ABCC2 and ABCC3 expression was low in brain microvessels, but high in rodent liver and lung vessels. Overall, most ABC transporters (with the exception of drug efflux transporters) were enriched in peripheral tissues compared to brain microvessels in humans, while in rodent species, additional ABC transporters were found to be enriched in brain microvessels. Conclusions: This study furthers the understanding of species similarities and differences in the expression patterns of ABC transporter genes; this is important for translational studies in drug development. In particular, CNS drug delivery and toxicity may vary among species depending on their unique profiles of ABC transporter expression in brain microvessels and BBB.

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…64 P-gp is present in many parts of the body, including the brain, kidney, liver, gastrointestinal tract and placenta, and its expression varies over circadian time. 26 At the BBB, P-gp is a key efflux transporter expressed on the apical surface of capillary endothelial cells to actively transport a wide range of substances, including drugs, toxins, and metabolites, from the brain back to the bloodstream. By preventing the accumulation of potentially harmful compounds, P-gp plays an important role in maintaining brain homeostasis and protecting against neurotoxicity.…”

“…Moreover, its presence is dramatically higher, from 10× to 1000×, in brain endothelial cells compared with other endothelial cells. 26 Using the published literature, we have constructed a visual chronological overview of BBB passage of P-glycoprotein effluxed substrates (Figure 4A). The brain permeability of the substrates was calculated from the cited reports according to their ZT, where ZT0 indicates lights on and ZT12 indicates lights off, and displayed on the graph according to the active and resting periods of diurnal and nocturnal animals.…”

The impact of ATP-binding cassette transporters in the diseased brain: Context matters

“…Notably, proteomics findings do not always align with transcriptomic data, emphasizing the importance of assessing transporter expression at the protein level. 26 ABCB1 and ABCG2’s dominance in the BBB is validated by proteomic data. Higher ABCG2 expression and lower expression of ABCB1 in humans indicate a potentially greater role of ABCG2 in the human BBB than inferred from studies in mice.…”

A zuranolone nanocrystal formulation enables solubility-independent in vivo study of pentylenetetrazol-induced seizures in a rat model

“…54 The current literature demonstrates an increase in transcript expression of efflux transporters and related enzymes during development. 55,56 Additionally, the expression and function of transporters are regulated by a variety of factors, including age, dose and length of the treatment, 55,57 nuclear receptors, 58 xenobiotics/ drugs 59 and a variety of inflammatory molecules. 60 Similarly to changes in the expression of drug transporters, changes in the developmental expression patterns of GABAA receptor subunits should be considered.…”