ABC Efflux Transporters and Solute Carriers in the Early Developing Brain of a Marsupial Monodelphis domestica (South American Gray Short-Tailed Opossum).

This study used a marsupial Monodelphis domestica, which is born very immature and most of its development is postnatal without placental protection. RNA-sequencing (RNA-Seq) was used to identify the expression of influx and efflux transporters (ATP-binding cassettes [ABCs] and solute carriers [SLCs]) and metabolizing enzymes in brains of newborn to juvenile Monodelphis. Results were compared to published data in the developing eutherian rat. To test the functionality of these transporters at similar ages, the entry of paracetamol (acetaminophen) into the brain and cerebrospinal fluid (CSF) was measured using liquid scintillation counting following a single administration of the drug along with its radiolabelled tracer [3H]. Drug permeability studies found that in Monodelphis, brain entry of paracetamol was already restricted at P5; it decreased further in the first week of life and then remained stable until the oldest age group tested (P110). Transcriptomic analysis of Monodelphis brain showed that expression of transporters and their metabolizing enzymes in early postnatal (P) pups (P0, P5, and P8) was relatively similar, but by P109, many more transcripts were identified. When transcriptomes of newborn Monodelphis brain and E19 rat brain and placenta were compared, several transporters present in the rat placenta were also found in the newborn Monodelphis brain. These were absent from E19 rat brain but were present in the adult rat brain. These data indicate that despite its extreme immaturity, the newborn Monodelphis brain may compensate for the lack of placental protection during early brain development by upregulating protective mechanisms, which in eutherian animals are instead present in the placenta.

Combined exposure to nanoplastics and metal oxide nanoparticles inhibits efflux pumps and causes oxidative stress in zebrafish embryos.

The ubiquity of microplastic/nanoplastics (MP/NPs) provides an opportunity for their interaction with other widely spread environmental contaminants. MP/NP and nanoparticles share a similar transport route from sources, production, and disposal. Metal oxide nanoparticles (nMOx) have varied industrial applications, and limited knowledge is available on their interaction with MP/NPs. The present study investigated the effect of NPs (1 mg/L) on the efflux of two nMOx, aluminium oxide nanoparticles (nAl2O3, 1 mg/L) and cerium oxide nanoparticles (nCeO2, 1 mg/L), and their combined toxicity to zebrafish embryos. The results illustrated increased accumulation of aluminium and cerium in the combined exposure group compared to the nMOx alone treatment. The presence of NPs exacerbated the oxidative stress caused by nAl2O3 and nCeO2, as evidenced by an increase in the concentration of reactive oxygen species (ROS), alteration of antioxidants, and lipid peroxidation. The integrated biomarker response (IBRv2) values showed the induction of an antioxidative response in NP + nAl2O3, whereas a decline in IBRv2 values was observed in NP + nCeO2. Our results indicate that NPs aggravated the accumulation of nMOx and their toxicity. The present work highlights that more attention should be paid to the discharge of these contaminants into the natural environment.

Chemical effects on dye efflux activity in live zebrafish embryos and on zebrafish Abcb4 ATPase activity.

ATP-binding cassette (ABC) transporter proteins include efflux pumps that confer multixenobiotic resistance to zebrafish embryos, a valuable toxico/pharmacological model. Here, we established an automated microscopy-based rhodamine B dye accumulation assay in which enhanced dye accumulation in live zebrafish embryos indicates inhibition of multixenobiotic efflux transporter activity. Twenty structurally divergent known substrates and/or inhibitors of human ABC transporters and environmentally relevant compounds were examined using this assay and the ATPase activity of recombinant zebrafish Abcb4 as readouts. These two assays confirmed that Abcb4 functions as an efflux transporter in zebrafish, whereas they gave discordant results for some of the tested substances. The dye accumulation assay in zebrafish embryos could be useful to screen environmental pollutants and other chemicals for efflux transporter interaction in a medium-throughput fashion.

[Pharmacokinetics mechanism of ABC efflux proteins-mediated seven features of compatibility].

ABC efflux proteins are a kind of transporters mediating diversified endogenous and exogenous efflux protein substrates across the plasma membrane by depending on the chemical energy released by ATP hydrolysis. As a vitally important functional membrane, it is widely found in various tissues and organs. The drug changes the expressions and/or functions of the transport proteins, which will affect the disposal process of substrate drugs corresponding to transporters in vivo, and finally lead to the pharmacokinetic interactions. The efflux proteins take part in the absorption, distribution, metabolism and excretion of drugs, and mainly consist of P-glycoprotein(P-gp), multidrug resistance associated protein(MRP) and breast cancer resistance protein(BCRP). The induction effect or inhibition effect of drugs on efflux protein plays a greatly significant role in the drug interaction produced by the compatibility of traditional Chinese medicine, which may be one of the important mechanisms of the theory of seven features of compatibility. In this article, the effects of seven features of compatibility on the ABC efflux transporters were reviewed, in order to reveal the roles of efflux protein in the herb-pairs compatibility, and provide new ideas for the mechanism and rationality of herb compatibility.

Pharmacokinetics mechanism of ABC efflux proteins-mediated seven features of compatibility / 中国中药杂志

ABC efflux proteins are a kind of transporters mediating diversified endogenous and exogenous efflux protein substrates across the plasma membrane by depending on the chemical energy released by ATP hydrolysis. As a vitally important functional membrane, it is widely found in various tissues and organs. The drug changes the expressions and/or functions of the transport proteins, which will affect the disposal process of substrate drugs corresponding to transporters , and finally lead to the pharmacokinetic interactions. The efflux proteins take part in the absorption, distribution, metabolism and excretion of drugs, and mainly consist of P-glycoprotein(P-gp), multidrug resistance associated protein(MRP) and breast cancer resistance protein(BCRP). The induction effect or inhibition effect of drugs on efflux protein plays a greatly significant role in the drug interaction produced by the compatibility of traditional Chinese medicine, which may be one of the important mechanisms of the theory of seven features of compatibility. In this article, the effects of seven features of compatibility on the ABC efflux transporters were reviewed, in order to reveal the roles of efflux protein in the herb-pairs compatibility, and provide new ideas for the mechanism and rationality of herb compatibility.

Is chemosensitisation by environmental pollutants ecotoxicologically relevant?

The active cellular efflux of toxicants is an efficient biological defense mode present in all organisms. By blocking this so-called multixenobiotic resistance transport-a process also referred to as chemosensitisation-, cellular bioaccumulation and the sensitivity of organisms towards environmental pollutants can increase. So far, a wide range of compounds, including pesticides, pharmaceuticals, fragrances, and surfactants, have been identified as chemosensitisers. Although, significant on a cellular level, the environmental impact of chemosensitisation on the organism level is not yet understood. Critically evaluating existing data, this paper identifies research needs to support our tentative conclusion that chemosensitisation may well enhance the risks of chemical exposure to aquatic organisms. Our conclusion is based on studies investigating the impact of individual chemicals and complex environmental mixtures on aquatic wildlife and a chemosensitiser mixture toxicity model which, however, is subject to great uncertainty due to substantial knowledge gaps. Those uncertainties include the inconsistent reporting of effect data, the lack of representative environmental contaminants tested for chemosensitisation, and the publishing of highly unreliable nominal exposure concentrations. In order to confirm the tentative conclusion of this paper, we require the significant and systematic investigation of a broader set of chemicals and environmental samples with a harmonised set of bioassays and rigorously controlled freely dissolved effect concentrations.