The activity of organic anion transporter-3: Role of dexamethasone

Wang, Haoxun; Liu, Chenchang; You, Guofeng

doi:10.1016/j.jphs.2017.12.011

Cited by 8 publications

(4 citation statements)

References 40 publications

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“…Our previous study had demonstrated the essential role of Nedd4-2 (a ubiquitin ligase) in the ubiquitination, surface expression, and transport activity of OAT3 [27]. Serum-and glucocorticoid-inducible kinases 1 (sgk1), PKC, janus tyrosine kinase 2 (JAK2) regulated OAT3 through Nedd4-2, which showed Nedd4-2 is molecular target for OAT3 regulation [27,37,38,46]. In this study, we further discovered proteasome was a novel target for regulation of OAT3 and stimulating OAT3 function can be achieved through inhibiting proteasomal activity.…”

Section: Discussionmentioning

confidence: 99%

“…Ixazomib, oprozomib, or delanzomib are all indicated in combination with dexamethasone, a synthetic glucocorticoid for the treatment of patients with multiple myeloma [61,65,66]. Our previous study showed dexamethasone stimulates OAT3 transport activity and membrane expression through the serum-and glucocorticoid-inducible kinases 1 signaling pathway, suggesting the stimulatory effect on OAT3 may be further magnified using ixazomib, oprozomib, and delanzomib in combination with dexamethasone [37].…”

Section: Discussionmentioning

confidence: 99%

“…Parental COS-7 and parental HEK293 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) (Corning, Tewksbury, MA, USA) supplemented with 10% fetal bovine serum (Gibco, Grand Island, NY, USA) at 37 • C in 5% CO 2 . Human OAT3-expressing (hOAT3) COS-7 cells and hOAT3-expressing HEK293 cells were established in our group [37,38]. The hOAT3 cells were cultured in DMEM supplemented with 10% fetal bovine serum and 0.2 mg/mL G418 sulfate (Gibco, Grand Island, NY, USA).…”

Section: Cell Culturementioning

confidence: 99%

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Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions

et al. 2021

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Organic anion transporter 3 (OAT3) is mainly expressed at the basolateral membrane of kidney proximal tubules, and is involved in the renal elimination of various kinds of important drugs, potentially affecting drug efficacy or toxicity. Our laboratory previously reported that ubiquitin modification of OAT3 triggers the endocytosis of OAT3 from the plasma membrane to intracellular endosomes, followed by degradation. Oral anticancer drugs ixazomib, oprozomib, and delanzomib, as proteasomal inhibitors, target the ubiquitin–proteasome system in clinics. Therefore, this study investigated the effects of ixazomib, oprozomib, and delanzomib on the expression and transport activity of OAT3 and elucidated the underlying mechanisms. We showed that all three drugs significantly increased the accumulation of ubiquitinated OAT3, which was consistent with decreased intracellular 20S proteasomal activity; stimulated OAT3-mediated transport of estrone sulfate and p-aminohippuric acid; and increased OAT3 surface expression. The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delanzomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug–drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

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Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions

et al. 2021

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“…As a result, this drug suffers from its broad and sustained activities. Dexamethasone has been implicated in pharmacokinetic interactions with a large number of drugs, probably due to its activity of regulating the expression of genes involved in drug metabolism and transport [72][73][74]. This glucocorticoid induces the expression of CES1 and CES2, but the induction is modest [75].…”

Section: Regulated Expression Of Carboxylesterases By Drugs and Diseamentioning

confidence: 99%

Carboxylesterases: Pharmacological Inhibition Regulated Expression and Transcriptional Involvement of Nuclear Receptors and other Transcription Factors

Shen

Shi

Yan

2019

Nuclear Receptor Research

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Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that determine the therapeutic efficacy and toxicity of ester/amide drugs. Without exceptions, all mammalian species studied express multiple forms of carboxylesterases. Two human carboxylesterases, CES1 and CES2, are major contributors to hydrolytic biotransformation. Recent studies have identified therapeutic agents that potently inhibit carboxylesterases-based catalysis. Some of them are reversible whereas others irreversible. The adrenergic antagonist carvedilol, for example, reversibly inhibits CES2 but this carboxylesterase is irreversibly inhibited by orlistat, a popular anti-obesity medicine. Kinetically, the inhibition occurs competitively, non-competitively or in combination, depending on a carboxylesterase. For example, the calcium channel blocker diltiazem competitively inhibits CES1 but non-competitively inhibits CES2. In addition to inhibited catalysis, several therapeutic agents or disease mediators have been shown to regulate the expression of carboxylesterases. For example, the antiepileptic drug phenobarbital induces both human and rodent carboxylesterases, whereas the antibiotic rifampicin induces human carboxylesterases only. Conversely, the proinflammatory cytokine interleukin-6 (IL-6) suppresses the expression of carboxylesterases across species, but depending on the concentrations of glucose in the culture medium. Transactivation, transrepression and altered mRNA stability contribute to the regulated expression. Several nuclear receptors are established to support the regulation including constitutive androstane receptor, glucocorticoid receptor and pregnane X receptor. In addition, non-ligand transcription factors are also involved in the regulation and exemplified by differentiated embryo chondrocyte-1, nuclear factor (erythroid-derived 2)-like 2 and tumor protein p53. These transcription factors coordinate the regulated expression of carboxylesterases, constituting a regulatory network for the hydrolytic biotransformation.

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