The role of dietary flavonoids for modulation of ATP binding cassette transporter mediated multidrug resistance

Flavonoids are widely existing compounds with enormous pharmacological effects from food and medicine. However, the low bioavailability in intestinal absorption and metabolism limits their clinical application. Intestinal efflux ABC (ATP binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), act as "pumping doors" to regulate the efflux of flavonoids from intestinal epithelial cells into the intestinal cavity or the systemic circulation. The present review describes the critical effect of ABC transporters involved in the efflux of flavonoids which depend on its efflux direction. And the role of flavonoids for modulation of intestinal ABC transporters was emphasized and several examples were given. We summarized that the resistance effect of flavonoid-mediated multidrug on ABC transporters may influence the bioavailability of drugs, bioactive ingredients and/or toxic compounds upon dietary uptake. Meanwhile, flavonoids functionalized as reversing agents of the ABC transporter may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that elucidation of the action and mechanism of the intestinal metabolic enzymes-efflux transporters coupling will lay a foundation for improving the bioavailability of flavonoids <i>in vivo</i> and increasing their clinical efficacy.

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intra-cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. Common polymorphisms and rare variants in ABC genes are associated with several complex phenotypes such as gout, gallstones, and cholesterol levels. Overexpression or amplification of specific drug efflux genes contributes to chemotherapy multidrug resistance. Conservation of the ATP-binding domains of ABC transporters defines the superfamily members, and phylogenetic analysis groups the 48 human ABC transporters into seven distinct subfamilies. While the conservation of ABC genes across most vertebrate species is high, there is also considerable gene duplication, deletion, and evolutionary diversification.

A Common R219K Variant of ATP-Binding Cassette Transporter A1 Gene Alters Atherometabolic Traits in Pregnant Women With Gestational Diabetes Mellitus

BackgroundATP-binding cassette transporter A1 (ABCA1) has important roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport, and is implicated in lipid-related disorders. Genetic variants are involved in the pathogenesis of gestational diabetes mellitus (GDM). The objective of this study was to investigate the association of rs2230806 (R219K), a single nucleotide polymorphism (SNP) in the lipid-related gene, with the risk of GDM and related traits.MethodsThe SNP, rs2230806, was genotyped, and clinical and metabolic parameters were determined in 660 GDM patients and 1,097 control subjects. Genetic associations with related traits were also analyzed.ResultsThe genotype distributions were similar in GDM patients and normal controls. However, significant differences in the variables examined in the study subjects were noted across the three genotypes. The genotype at the rs2230806 polymorphism was significantly associated with HDL-cholesterol (HDL-C) levels and atherogenic index (AI) values in GDM patients and total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in control subjects. Subgroup analysis showed that the polymorphism was associated with diastolic blood pressure, in addition to HDL-C levels and AI, in overweight/obese GDM patients, while it was associated with TC levels, AI, pre-pregnancy body mass index (BMI), and BMI at delivery in non-obese GDM patients. In addition, this polymorphism was associated with TC, LDL-C, and apoB levels in overweight/obese control subjects.ConclusionsThe rs2230806 polymorphism in the ABCA1 gene was associated with variations in atherometabolic traits in GDM patients, with characteristics of BMI dependency, but not with GDM. Our findings highlight a link between related phenotypes in women with GDM and genetic factors.

Comparative Toxicological Evaluation of Tattoo Inks on Two Model Organisms

Tattooing is a technique that introduces colored substances under the skin in order to color it permanently. Decomposition products of tattoo pigments produce numerous damages for the skin and other organs. We studied the effects of a commercial red ink tattoo, PR170, on Xenopus laevis embryos and Daphnia magna nauplii using concentrations of 10, 20, and 40 mg/L. For Xenopus, we applied the FETAX protocol analyzing survival, malformations, growth, heart rate, and the expression of genes involved in the development. In D. magna, we evaluated the toxicity with an immobilization test. Moreover, we investigated the production of ROS, antioxidant enzymes, and the expression of the ATP-binding cassette in both models. Our results indicate that PR170 pigment has nanoparticle dimensions, modifies the survival and the ATP-binding cassette activity, and induces oxidative stress that probably produces the observed effects in both models. Deformed embryos were observed in Xenopus, probably due to the modification of expression of genes involved in development. The expression of pro-inflammatory cytokines was also modified in this amphibian. We think that these effects are due to the accumulation of PR170 and, in particular, to the presence of the azoic group in the chemical structure of this pigment. Further studies needed to better understand the effects of commercial tattoo inks.

Identification of an ATP-Binding Cassette Transporter Implicated in Aluminum Tolerance in Wild Soybean (Glycine soja)

The toxicity of aluminum (Al) in acidic soil limits global crop yield. The ATP-binding cassette (ABC) transporter-like gene superfamily has functions and structures related to transportation, so it responds to aluminum stress in plants. In this study, one half-size ABC transporter gene was isolated from wild soybeans (Glycine soja) and designated GsABCI1. By real-time qPCR, GsABCI1 was identified as not specifically expressed in tissues. Phenotype identification of the overexpressed transgenic lines showed increased tolerance to aluminum. Furthermore, GsABCI1 transgenic plants exhibited some resistance to aluminum treatment by ion translocation or changing root components. This work on the GsABCI1 identified the molecular function, which provided useful information for understanding the gene function of the ABC family and the development of new aluminum-tolerant soybean germplasm.

Bixin and fucoxanthin sensitize human lung cancer and cervical cancer cell to cisplatin in vitro

Objective Cisplatin is a conventional anticancer drug that generates reactive oxygen species and causes apoptosis. However, many cancer cells develop alterations in the ATP binding cassette transporter responsible for the uptake and efflux process, which leads to resistance. Many natural products have shown potential to compete with ATP binding cassette transporter and may sensitize resistant cells to cisplatin. Studies have shown pro-oxidant effect of carotenoids that promote apoptosis of cancer cells. Bixin and fucoxanthin are well-known carotenoids with known antioxidant properties, however their bioactivity in lung cancer cells, clinically known to develop resistance due to ATP binding cassette transporter, has been minimally studied. This study is the first to investigate the potential of bixin and fucoxanthin to sensitize human lung cancer cell line, A549 and cervical cancer cell line, HeLa, to cisplatin. Drug combination method developed by Chou and Talalay theorem was employed. Result Employing the best combination ratio, this study shows selective sensitization of cancer cells to cisplatin after bixin and fucoxanthin treatment. Further study on the mechanism of action in specific types of cancer cells is warranted. It may improve cisplatin sensitivity in tumors and rational use of cancer drugs. Graphical Abstract