Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), ...albendazole sulfone (ABZSO
) and albendazole 2-aminosulphone (ABZSO
-NH
). ABZSO and ABZSO
are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was
transported by ABCG2. The aim of this work is to correlate the
interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using
transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO
and ABZSO
-NH
are
substrates of both.
assays carried out with wild-type and Abcg2
lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2
mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly
substrates of ABCG2 and actively secreted into milk by ABCG2.
The ABCG2 transporter plays a key role in pharmacological and toxicological processes, affecting bioavailability, tissue accumulation and milk secretion of its substrates. This protein is expressed ...in several biological barriers acting as a protective mechanism against xenobiotic exposure by pumping out a broad range of compounds. However, its induced expression during lactation in alveolar cells of mammary gland represents a relevant route for active transport of unwanted chemicals into milk. This work aimed to characterize the involvement of ABCG2 in systemic exposure and milk secretion of the flukicide nitroxynil. Using MDCK-II cells overexpressing the transporter, we showed that nitroxynil is an in vitro substrate of different species variants of ABCG2. Moreover, using wild-type and Abcg2
mice, we showed that murine Abcg2 clearly affects plasma levels of nitroxynil. We also reported differences in nitroxynil accumulation in several tissues, with almost 2-fold higher concentration in kidney, small intestine and testis of Abcg2
mice. Finally, we proved that nitroxynil secretion into milk was also affected by Abcg2, with a 1.9-fold higher milk concentration in wild-type compared with Abcg2
mice. We conclude that ABCG2 significantly impacts nitroxynil biodistribution by regulating its passage across biological barriers.
Thiabendazole (TBZ) is a broad–spectrum anthelmintic and fungicide used in humans, animals, and agricultural commodities. TBZ residues are present in crops and animal products, including milk, posing ...a risk to food safety and public health. ABCG2 is a membrane transporter which affects bioavailability and milk secretion of xenobiotics. Therefore, the aim of this work was to characterize the role of ABCG2 in the in vitro transport and secretion into milk of 5–hydroxythiabendazole (5OH–TBZ), the main TBZ metabolite. Using MDCK–II polarized cells transduced with several species variants of ABCG2, we first demonstrated that 5OH–TBZ is efficiently in vitro transported by ABCG2. Subsequently, using Abcg2 knockout mice, we demonstrated that 5OH–TBZ secretion into milk was affected by Abcg2, with a more than 2–fold higher milk concentration and milk to plasma ratio in wild–type mice compared to their Abcg2–/– counterpart.
•5OH-thiabendazole is in vitro transported by murine, human, ovine, and bovine ABCG2.•In vitro transport of 5OH-thiabendazole is affected by the bovine Y581S SNP.•ABCG2 transporter increases milk secretion of 5OH-thiabendazole.
The ATP‐binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and ...secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6‐hydroxymelatonin, and 6‐sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK‐II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild‐type and Abcg2−/− mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2−/− mice was between 1.5 and 6‐fold higher compared to the wild‐type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6‐sulfatoxymelatonin in Abcg2−/− mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild‐type compared with Abcg2−/− lactating female mice. In addition, melatonin metabolites showed a higher milk‐to‐plasma ratio in wild‐type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity.
In veterinary field, drug exposure during milk production in dairy cattle is considered a major health problem which concerns dairy consumers. The induced expression of the ABC transporter G2 (ABCG2) ...in the mammary gland during lactation plays a significant role in the active secretion of many compounds into milk. The main objective of this study was to determine the involvement of ABCG2 in the secretion into milk of the antiparasitic clorsulon in sheep as well as the possible effect of the coadministration of model ABCG2 inhibitors such as macrocyclic lactones on this process. Cells transduced with the ovine variant of ABCG2 were used to carry out
in vitro
transepithelial transport assays in which we showed that clorsulon is a substrate of the ovine transporter. In addition, ivermectin and abamectin significantly inhibited clorsulon transport mediated by ovine ABCG2.
In vivo
interactions were studied in Assaf sheep after coadministration of clorsulon (in DMSO, 2 mg/kg, s.c.) with ivermectin (Ivomec
®
, 0.2 mg/kg, s.c.) or abamectin (in DMSO, 0.2 mg/kg, s.c.). After ivermectin and abamectin treatment, no relevant statistically significant differences in plasma levels of clorsulon were reported between the experimental groups since there were no differences in the area under the plasma concentration-curve (AUC) between clorsulon treatment alone and coadministration with macrocyclic lactones. With regard to milk, total amount of clorsulon, as percentage of dose excreted, did not show statistically significant differences when macrocyclic lactones were coadministered. However, the AUC for clorsulon significantly decreased (
p
< 0.05) after coadministration with ivermectin (15.15 ± 3.17 μg h/mL) and abamectin (15.30 ± 3.25 μg h/mL) compared to control group (20.73 ± 4.97 μg h/mL). Moreover, milk parameters such as half-life (
T
1/2
) and mean residence time (MRT) were significantly lower (
p
< 0.05) after coadministration of macrocyclic lactones. This research shows that the milk pharmacokinetics of clorsulon is affected by the coadministration of ABCG2 inhibitors, reducing drug persistence in milk.
ABCG2 is an ATP-binding cassette efflux transporter that is expressed in absorptive and excretory organs such as liver, intestine, kidney, brain and testis where it plays a crucial physiological and ...toxicological role in protecting cells against xenobiotics, affecting pharmacokinetics of its substrates. In addition, the induction of ABCG2 expression in mammary gland during lactation is related to active secretion of many toxicants into milk. In this study, the in vitro interactions between ABCG2 and three pesticides flupyradifurone, bupirimate and its metabolite ethirimol were investigated to check whether these compounds are substrates and/or inhibitors of this transporter. Using in vitro transepithelial assays with cells transduced with murine, ovine and human ABCG2, we showed that ethirimol and flupyradifurone were transported efficiently by murine Abcg2 and ovine ABCG2 but not by human ABCG2. Bupirimate was not found to be an in vitro substrate of ABCG2 transporter. Accumulation assays using mitoxantrone in transduced MDCK-II cells suggest that none of the tested pesticides were efficient ABCG2 inhibitors, at least in our experimental conditions. Our studies disclose that ethirimol and flupyradifurone are in vitro substrates of murine and ovine ABCG2, opening the possibility of a potential relevance of ABCG2 in the toxicokinetics of these pesticides.
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•Bupirimate is not an in vitro substrate of the murine Abcg2 transporter.•Ethirimol and flupyradifurone are in vitro substrates of murine and ovine ABCG2.•None of the tested pesticides are in vitro substrates of human ABCG2.•No relevant ABCG2 inhibition is suggested in mitoxantrone accumulation assays.
Clorsulon is a benzenesulfonamide drug that is effective in treating helminthic zoonoses such as fascioliasis. When used in combination with the macrocyclic lactone ivermectin, it provides high ...broad-spectrum antiparasitic efficacy. The safety and efficacy of clorsulon should be studied by considering several factors such as drug-drug interactions mediated by ATP-binding cassette (ABC) transporters due to their potential effects on the pharmacokinetics and drug secretion into milk. The aim of this work was to determine the role of ABC transporter G2 (ABCG2) in clorsulon secretion into milk and the effect of ivermectin, a known ABCG2 inhibitor, on this process. Using
transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we report that clorsulon was transported
by both transporter variants and that ivermectin inhibited its transport mediated by murine Abcg2 and human ABCG2. Wild-type and Abcg2
lactating female mice were used to carry out
assays. The milk concentration and the milk-to-plasma ratio were higher in wild-type mice than in Abcg2
mice after clorsulon administration, showing that clorsulon is actively secreted into milk by Abcg2. The interaction of ivermectin in this process was shown after the coadministration of clorsulon and ivermectin to wild-type and Abcg2
lactating female mice. Treatment with ivermectin had no effect on the plasma concentrations of clorsulon, but the milk concentrations and milk-to-plasma ratios of clorsulon decreased in comparison to those with treatment without ivermectin, only in wild-type animals. Consequently, the coadministration of clorsulon and ivermectin reduces clorsulon secretion into milk due to drug-drug interactions mediated by ABCG2.
Seventeen phenolic compounds that are allowed to be used in the European food industry as aromatizants or antioxidants or that are naturally present in plants were tested for their ability to inhibit ...19 strains of Staphylococcus aureus by using a standardized paper disc assay. Most of the strains assayed were foodborne (dairy and meat products). Human isolates and/or strains recommended for testing antimicrobial agents were also included in the study, and some of the test strains were enterotoxin producers. When the content was 200 microg/disc, various phenolic compounds had shown antimicrobial activity against all (hydroquinone, thymol, carvacrol, butylated hydroxyanisole, octyl gallate, and tannic acid) or most (gallic acid, propyl gallate, and ellagic acid) of the S. aureus strains tested. Significant differences in the inhibition zones (p < 0.05) among strains of the same, or similar, origin and among the different origins were observed for most of the phenolic compounds that showed antimicrobial activity for all or most of the strains tested.
Antibacterial activity against nineteen Staphylococcus aureus strains of five phenolic compounds (PCs) (hydroquinone, carvacrol, thymol, gallic acid and octyl gallate) was assessed in binary ...combinations with butylated hydroxyanisole (BHA). An antagonistic effect between BHA and each of the other PCs tested in combination was observed against 67% (for BHA + thymol) to 95% (BHA + octyl gallate) of the S. aureus strains, and no interaction effect was observed for the rest of the strains. Only slight differences in the antagonistic effect were detected among the strains of the different origins, between 80% (dairy) to 88% (meat). Concerning to the antioxidant activity, the combinations studied were mostly additive, with the exception of BHA + carvacrol and BHA + thymol that were antagonistic. It is concluded that the antagonic/no interaction antimicrobial effects of BHA + PCs against S. aureus are of interest to the food industry as they may determine the effectivity of active antimicrobial individual PCs and then, the safety of foods, when they coincide voluntarily or accidentally in foods.
•Antagonistic effect between BHA and the other PCs was observed for most S. aureus strains.•The strain is a factor that can influence the interaction results, from antagonistic to no interaction effects.•Three of the BHA + PC combinations showed an additive antioxidant effect.
Six pure phenolic compounds (hydroquinone, thymol, carvacrol, butylated hydroxyanisole, gallic acid, and octyl gallate) were tested for their minimum inhibitory concentration (MIC) and minimum ...bactericidal concentration (MBC) against several strains of Staphylococcus aureus isolated from dairy and meat products. In addition, S. aureus reference strains (American Type Culture Collection) for antimicrobial studies and/or isolated from human infections and outbreaks of food poisoning were included in the study. Of the compounds tested, octyl gallate and hydroquinone were the most effective against S. aureus (mean MIC values of 20.89 and 103.05 μg/mL, respectively) and carvacrol and thymol the least (mean MIC values of about 413 μg/mL). The mean MBC values were 40.84, 194.37, 417.46, and 581.90 μg/mL for octyl gallate, hydroquinone, carvacrol, and thymol, respectively. Meat isolates were more resistant than those of dairy origin to hydroquinone, gallic acid, and octyl gallate, as well as to penicillin G (used as a control of the methodology used); gallic acid and penicillin G showed the highest differences in MIC values between the groups of strains (about 10 and 200 times, respectively). On the other hand, when we tested the isolates included in each group of strains (dairy, meat, and other/mixed sources) we only detected significant differences (p < 0.05) among dairy and isolates from other/mixed sources for hydroquinone and thymol, respectively. However, strains of meat origin exhibited significant differences among each other (p < 0.05) to most of the phenolic compounds tested (hydroquinone, carvacrol, gallic acid, and octyl gallate). The relationship between MICs and MBCs for each of the phenolic compounds tested suggested a bactericidal mechanism of action against S. aureus. Gallic acid and octyl gallate exhibited the highest antioxidant capacity and thymol and carvacrol the lowest. So, octyl gallate is an agent with both antimicrobial and antioxidant properties, which would be of interest to use in the food industry.
