The Role of P-Glycoprotein in Decreasing Cell Membranes Permeability during Oxidative Stress

Shchulkin, A. V.; Abalenikhina, Yu. V.; Erokhina, Pelageya D.; Chernykh, I. V.; Yakusheva, E. N.

doi:10.1134/s0006297921020085

Cited by 19 publications

(17 citation statements)

References 38 publications

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“…At higher concentrations, HP produced excessive oxidative stress, which caused damages of cell membrane, retrieval of transporters from membrane, and disruption of RNA structure, thus reducing the activities and gene expressions of ABC transporters. [ 45 ] These phenomena provided an explanation for the controversial results that oxidative stress has been considered as the main reason for both upregulation and downregulation of ABC transporters. [ 46,47 ]…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress‐mediated up‐regulation of ABC transporters in lung cancer cells

Yuan

Zhu

et al. 2022

J Biochem & Molecular Tox

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This paper aimed to evaluate the role of oxidative stress in the regulation of ABC transporters in human lung cancer (A549) cells facing substrate (doxorubicin, DOX) and nonsubstrate (ethanol, ETH and hydrogen peroxide, HP) chemicals. After 24‐h treatment, all the chemicals caused significant cytotoxicity as reflected by the reduction in cell viability and the increase in reactive oxygen species (ROS) levels. Depending on the rescuing effects of ROS scavenger including glutathione (GSH) and Vitamin C, the toxicity dependence on oxidative stress were found to be HP > ETH > DOX. The addition of transporter inhibitors significantly enhanced the ROS levels and death‐inducing effects of chemicals, indicating the universal detoxification function of ABC transporters. At moderate ROS levels (about 3–4‐folds of control levels, caused by 10 μM DOX, 400 mM ETH, and 400 μM HP), all the three chemicals induced the gene expressions and activities of ABC transporters, but these values decreased at too high ROS levels (8.36‐folds of control levels) caused by HP at LC50 (800 μM). Such induction could be attenuated by GSH and KCZ, and was completely abolished by 50 μM KCZ, indicating an important role of oxidative stress and pregnane X receptor (PXR) in the induction of ABC transporters. Finally, this paper revealed the critical role of oxidative stress in the modulation of ABC transporters by either substrate or nonsubstrate chemicals during 24‐h treatment. Such information should be beneficial for overcoming ABC transporter‐mediated multidrug resistance.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress‐mediated up‐regulation of ABC transporters in lung cancer cells

Yuan

Zhu

et al. 2022

J Biochem & Molecular Tox

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“…В ходе настоящего исследования была оценена роль транскрипционных факторов Nrf2, HIF1a, CAR и PXR, которые активируются при окислительном стрессе [17,[33][34][35] и гипотетически могут повышать экспрессию Pgp.…”

Section: Discussionunclassified

“…Концентрации прооксидантов и длительность экспозиции выбирали в соответствии с результатами предварительных экспериментов, в которых было доказано их индуцирующее действие на Pgp [17,21].…”

Section: культивирование клетокunclassified

“…В исследованиях, выполненных в нашей лаборатории на клетках линии Caco-2, показано, что кратковременное (3 ч) воздействие H 2 O 2 в концентрации 10 и 50 мкМ приводило к понижению активности Pgp, а в концентрации 100 мкМ − еще и к снижению количества белка-транспортера. Увеличение длительности экспозиции до 24 и 72 ч выявило индукцию Pgp при низких концентрациях H 2 O 2 (0.1−1 мкМ, 24 ч и 10 мкМ, 72 ч), а также снижение количества и активности Pgp при повышении концентрации H 2 O 2 до 100 мкМ и выше [17].…”

Section: Introductionunclassified

“…Считается, что снижение количества Pgp в условиях ОС связано с повреждением молекулы белка-транспортера активными формами кислорода (АФК), однако механизмы повышения экспрессии Pgp не установлены. Предполагается, что в этом процессе могут участвовать транскрипционные факторы Nrf2 и HIF1 [17,18]. Цель нашей работы состояла в изучении механизмов регуляции Pgp при развитии ОС.…”

Section: Introductionunclassified

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Mechanisms of P-Glycoprotein Regulation Under Exogenous and Endogenous Oxidative Stress <i>In Vitro</i>

et al. 2022

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We investigated the mechanisms of P-glycoprotein (P-gp) transporter regulation in Caco-2 cells under exogenous and endogenous oxidative stress (OS). Exogenous OS was modeled by exposure of the growth medium to hydrogen peroxide at concentrations of 0.1, 0.5, and 1 M for 24 h or 10 M for 72 h. Endogenous OS was modeled by incubating cells with DL-buthionine sulfoximine (BSO, gamma-glutamylcysteine synthetase inhibitor) at a concentration of 10, 50, and 100 M for 24 h. The levels of intracellular reactive oxygen species (ROS) were assessed using MitoTracker Red CM-H2XRos fluorescent probes. Relative P-gp contents were analyzed using Western blot. Exogenous and endogenous OS was shown to increase relative to P-gp contents. An important role played by the Nrf2-Keap1 signaling pathway in increasing the P-gp contents under H2O2-induced exogenous OS was revealed using specific inhibitors. The transcription factor HIF1 is involved in the regulation of the P-gp levels under 24-hour exogenous OS, and the transcription factor CAR is involved in the regulation of transporter levels under 72-hour OS. All tested transcription factors and signaling pathways are involved in P-gp induction under endogenous OS. Most likely, this is associated with the bimodal effect of BSO on Pgp. On the one hand, BSO induces the development of OS; on the other, BSO, as a xenobiotic, is able to stimulate PXR and CAR, which, in turn, increase the P-gp contents.

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Association between α‐defensin 5 and the expression and function of P‐glycoprotein in differentiated intestinal Caco‐2 cells

Yasuda

Kubota

Okamoto

et al. 2023

Biopharm & Drug Disp

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Abstractα‐Defensin 5 is known to be secreted by Paneth cells in the small intestine and plays an important role in eliminating pathogenic microorganisms. It has been reported that a decrease in α‐defensin 5 level in the human small intestine is a risk of inflammatory bowel disease (IBD). Furthermore, P‐glycoprotein (P‐gp), a member of the ATP‐binding cassette transporter superfamily, encoded by the ABCB1/MDR1 gene, plays an important role in the front line of host defense by protecting the gastrointestinal barrier from xenobiotic accumulation and may contribute to the development and persistence of IBD. Therefore, we examined the relationship between α‐defensin 5 and the expression and function of P‐gp using a human gastrointestinal model cell line (Caco‐2). We found that MDR1 mRNA and P‐gp protein level were increased in Caco‐2 cells as well as α‐defensin 5 secretion corresponded with the duration of cell culture. Exposure to α‐defensin 5 peptide and recombinant tumor necrosis factor‐α (TNF‐α) significantly increased the expression and function P‐gp. The mRNA levels of interleukin (IL)‐8, IL‐6, TNF‐α, IL‐1β, and IL‐2 were also increased following exposure to TNF‐α, similar to α‐defensin 5 treatment. These results suggest that α‐defensin 5 regulates P‐gp expression and function by increasing TNF‐α expression in Caco‐2 cells.

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The Role of P-Glycoprotein in Decreasing Cell Membranes Permeability during Oxidative Stress

Cited by 19 publications

References 38 publications

Oxidative stress‐mediated up‐regulation of ABC transporters in lung cancer cells

Oxidative stress‐mediated up‐regulation of ABC transporters in lung cancer cells

Mechanisms of P-Glycoprotein Regulation Under Exogenous and Endogenous Oxidative Stress <i>In Vitro</i>

Association between α‐defensin 5 and the expression and function of P‐glycoprotein in differentiated intestinal Caco‐2 cells

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