The Contribution of Human OCT1, OCT3, and CYP3A4 to Nitidine Chloride–Induced Hepatocellular Toxicity

Li, Liping; Tu, Meijuan; Yang, Xi; Sun, Siyuan; Wu, Xiaodan; Zhou, Hui; Zeng, Su; Jiang, Huidi

doi:10.1124/dmd.113.056689

Cited by 37 publications

(20 citation statements)

References 57 publications

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“…Interestingly, NC was found to be a candidate substrate of OCT1 and OCT3 that transfer NC into hepatocytes. Moreover, MATE1 makes NC leave from hepatocytes, while CYPs contributed to NC metabolism such as CYP3A4 and attenuated the hepatic toxicity of NC [23]. TOP1 and TOP2A are key tumor drivers in liver cancer [24], suggesting that TOP1 and TOP2A might be promising targets for treating malignances [25].…”

Section: Liver Cancermentioning

confidence: 99%

Antitumor functions and mechanisms of nitidine chloride in human cancers

Cui¹,

Wu²,

Cao³

et al. 2020

J. Cancer

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Nitidine chloride (NC), a quaternary ammonium alkaloid, exhibits multiple biological activities, including antimalarial, antifungal, and antiangiogenesis. Recently, NC has been characterized to perform antitumor activity in a variety of malignancies. NC has been identified to suppress cell proliferation, stimulate apoptosis, and induce cell cycle arrest, retard migration, invasion and metastasis. Moreover, NC is reported to sensitize cancer cells to chemotherapeutic drugs. In this review article, we describe the functions of NC in human cancers and discuss the molecular insight into NC-involved antitumor feature. This review article will stimulate the deeper investigation for using NC as a potent agent for the management of cancer patients.

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Section: Liver Cancermentioning

confidence: 99%

Antitumor functions and mechanisms of nitidine chloride in human cancers

Cui¹,

Wu²,

Cao³

et al. 2020

J. Cancer

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“…Li et al . suggested that NTD is metabolized by hepatic enzymes such as P450, which mainly catalyzes the oxidation of drugs and, therefore, concluded that the oral bioavailability of NTD is probably very low . In the present study, however, oral NTD concentrate significantly inhibited tumor growth (Fig.…”

Section: Discussionmentioning

confidence: 44%

Anti‐tumor effects of nitidine on camptothecin‐resistant A549 cells in a xenograft mouse model

Taira

Inafuku

Oku

2016

Traditional & Kampo Medicine

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Aim Nitidine (NTD) has been reported to specifically inhibit the growth of human A549 non‐small‐cell lung cancer cells via selective intracellular accumulation. Our recent study showed that NTD preferentially accumulates in camptothecin‐resistant A549 cells (CRC) compared with normal A549 cells (nA549) in vitro. Here, we examined the in vivo anti‐tumor effects of NTD on CRC‐derived tumors and oral treatment on nA549 using a xenograft mouse model. Methods Cancer cells were intradermally inoculated into the back of mice. Then, 100 µg NTD was injected i.p. into the nA549‐ or CRC‐derived tumor‐bearing mice. To confirm the anti‐tumor effects of oral NTD, the nA549‐transplanted mice were fed a diet containing NTD concentrate prepared from Toddalia asiatica Lam. Results The anti‐tumor effect of NTD (i.p.) manifested earlier in CRC‐derived tumors than in the A549‐derived tumors. Oral NTD concentrate also significantly inhibited the growth of the nA549‐derived tumors. NTD was detected in the tumor but not in other tissues in the NTD concentrate‐fed mice. Conclusion CRC‐derived tumor was more susceptible to NTD treatment than nA549‐derived tumor. Furthermore, the anti‐tumor effect of oral NTD and its preferential accumulation in tumor tissues have been demonstrated for the first time. This may be useful for the development of safe anti‐cancer drugs.

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“…In addition, human multidrug and toxin extrusion 1 (hMATE1), an H + ‐coupled organic cation exporter, is also expressed in the brush border membrane of proximal tubule cells (Omote et al, ; Kusuhara and Sugiyama, ). Because NC was also identified as a substrate of hMATE1 in our previous study (Li et al, ), MATE1 might mediate the efflux of NC from renal tubular epithelial cells and alleviate NC‐induced nephrotoxicity.…”

Section: Introductionmentioning

confidence: 82%

“…The concentrations of MPP + and NC in the cellular uptake and tissue samples were determined by the modified LC–MS/MS method (Li et al, ) using an Agilent 1290/6460 LC–MS with a triple quadrupole mass spectrometer. Two or eight volumes of acetonitrile containing 90 ng mL ‐1 loratadine as an internal standard (IS) were added to the cell lysates or tissue samples, respectively, to precipitate proteins.…”

Section: Methodsmentioning

confidence: 99%

“…Cell membrane transporters and drug metabolic enzymes play crucial roles in the disposition of xenobiotics in vivo (Rappold et al, ; Yonezawa and Inui, ; Liu et al, ); thus, they might also contribute to drug‐induced toxicity. Our previous study demonstrated that NC is a high affinity substrate of human organic cation transporters 1 and 3 (hOCT1 and hOCT3), which mediated the hepatocellular uptake of NC and subsequently caused hepatotoxicity (Li et al, ). Additionally, we also found that NC was a substrate of CYPs, such as CYP3A4, which mediated NC metabolism and attenuated the toxicity of NC in hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

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Role of OCT2 and MATE1 in renal disposition and toxicity of nitidine chloride

Song

Weng

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSENitidine chloride (NC), a benzophenanthridine alkaloid, has various biological properties including anticancer and analgesic activities. The aim of the present study was to evaluate the role of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) in the renal disposition and nephrotoxicity of NC. EXPERIMENTAL APPROACHMDCK cells stably expressing human OCT2 and/or hMATE1 were used to investigate the OCT2-and MATE1-mediated transport of NC. In addition, the accumulation of NC and its potential toxicity were studied in rat primary-cultured proximal tubular (rPCPT) cells and in rats in vivo. KEY RESULTSNC was found to be a high-affinity substrate of both OCT2 and MATE1 with high cytotoxicity in MDCK-hOCT2/hMATE1 and MDCK-hOCT2 compared to mock cells. The OCT2 inhibitors, cimetidine and (+)-tetrahydropalmatine ((+)-THP), significantly reduced NC accumulation and cytotoxicity in MDCK-hOCT2, MDCK-hOCT2/hMATE1 and rPCPT cells. Severe kidney damage with high levels of blood urea nitrogen and lactate dehydrogenase (LDH), reduced levels of alkaline phosphatase (ALP) and pathological changes were found in rats after 20 days of successive i.v. doses of NC (5 mg·kg À1 ·day À1 ). Concomitantly, the concentration of NC in the kidney reached similar high levels at 2 h after the last dose of the 20 day treatment as those observed at 0.5 h after a single i.v. dose of 5 mg·kg À1 . CONCLUSIONS AND IMPLICATIONSOur data indicate that NC-induced nephrotoxicity might be mainly attributed to OCT2-mediated extensive renal uptake and weak tubular secretion by MATE1.Abbreviations ASP + , 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide; ESI, electrospray ionization; HPC, hydroxypropyl cellulose; MATE1, multidrug and toxin extrusion 1; MPP

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The Contribution of Human OCT1, OCT3, and CYP3A4 to Nitidine Chloride–Induced Hepatocellular Toxicity

Cited by 37 publications

References 57 publications

Antitumor functions and mechanisms of nitidine chloride in human cancers

Antitumor functions and mechanisms of nitidine chloride in human cancers

Anti‐tumor effects of nitidine on camptothecin‐resistant A549 cells in a xenograft mouse model

Role of OCT2 and MATE1 in renal disposition and toxicity of nitidine chloride

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