Analysis of drug transporter expression in syncytiotrophoblast derived from human placental stem cells: Expression and function of efflux transporters

Article

Author: Nishimura, Ayako ; Ueda, Ayami ; Furugen, Ayako ; Umazume, Takeshi ; Kobayashi, Masaki ; Narumi, Katsuya ; Sawada, Riko

OBJECTIVEThe placenta is a vital organ for exchanging nutrients, endogenous substances, and xenobiotics between mother and fetus. The syncytiotrophoblast (ST) is crucial in maintaining the placental barrier. Human trophoblast stem cells (hTSCs) have been recently established; however, their utility in studying placental transport functions has not been fully elucidated. This study investigated the expression and function of transporters in hTSC-derived ST cells.METHODSTS^CT cells, as hTSCs, were differentiated into ST-like cells (ST-TS^CT), and the gene expression of 84 transporters in ST-TS^CT cells was evaluated using a PCR array. BeWo cells, a widely used trophoblast model, were used for comparison. BeWo cells were differentiated into ST-like cells using forskolin [BeWo (FK)]. The protein levels of efflux transporters were examined by western blotting, and functional assays were performed using typical fluorescent substrates.RESULTSTransporter gene expression levels were higher in ST-TS^CT than in BeWo (FK) cells, with 27 genes showing more than a 3-fold increase. Ten of these genes were exclusively expressed in ST-TS^CT. Western blotting revealed the presence of efflux transporters, including P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 2 (MRP2/ABCC2). Furthermore, the accumulation of typical substrates (Rhodamine123 for P-gp, Hoechst33342 and BODIPY™ FL Prazosin for BCRP, and 5(6)-carboxy-2',7'-dichlorofluorescein diacetate for MRP) significantly increased when transporter inhibitors (elacridar, Ko143, and MK571) were applied.CONCLUSIONThis study showed higher transporter expression in ST-TS^CT than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TS^CT is valuable for investigating placental transport functions.

02 Jan 2025·Toxicology Mechanisms and Methods

Studies on pharmacokinetic properties and intestinal absorption mechanism of sanguinarine chloride: in vivo and in situ

Article

Author: Liu, Wei ; Zeng, Jianguo ; Liu, Zhiqin ; Dong, Zhen ; Chang, Guanyu ; Xu, Yufeng ; Yang, Zihui ; Wang, Hongting ; Sun, Wenqing

Sanguinarine (SAN) is an alkaloid with multiple biological activities, mainly extracted from Sanguinaria canadensis or Macleaya cordata. The low bioavailability of SAN limits its utilization. At present, the nature and mechanism of SAN intestinal absorption are still unclear. The pharmacokinetics, single-pass intestinal perfusion test (SPIP), and equilibrium solubility test of SAN in rats were studied. The absorption of SAN at 20, 40, and 80 mg/L in different intestinal segments was investigated, and verapamil hydrochloride (P-gp inhibitor), celecoxib (MPR2 inhibitor), and ko143 (BCRP inhibitor) were further used to determine the effect of efflux transporter proteins on SAN absorption. The equilibrium solubility of SAN in three buffer solutions (pH 1.2, 4.5 and 6.8) was investigated. The oral pharmacokinetic results in rats showed that SAN was rapidly absorbed (T_max=0.5 h), widely distributed (Vz/F = 134 L/kg), rapidly metabolized (CL = 30 L/h/kg), and had bimodal phenomena. SPIP experiments showed that P-gp protein could significantly affect the effective permeability coefficient (P_eff) and apparent absorption rate constant (Ka) of SAN. Equilibrium solubility test results show that SAN has the best solubility at pH 4.5. In conclusion, SAN is a substrate of P-gp, and its transport modes include efflux protein transport, passive transport and active transport.

15 Nov 2024·ACS Chemical Biology

Modulation of ABCG2 Transporter Activity by Ko143 Derivatives

Article

Author: Wen, Po-Chao ; Ni, Dongchun ; Dehghani-Ghahnaviyeh, Sepehr ; Tajkhorshid, Emad ; Rasouli, Ali ; Kowal, Julia ; Sadurni, Anna ; Locher, Kaspar P. ; Bang-Soerensen, Rose ; Tinzl-Zechner, Melanie ; Irobalieva, Rossitza N. ; Stahlberg, Henning ; Altmann, Karl-Heinz ; Yu, Qin

ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their in vitro modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved in vivo stability.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	Netherlands	Netherlands Cancer Insitute	01 Apr 2002

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