TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Xiaocui Li,Xiaowen Ou,Guangkuo Luo,Xiaojun Ou,Yushan Xie,Mengdi Ying,Wei Qu,Huilin Zuo,Xiaoxiao Qi,Ying Wang,Zhongqiu Liu,Lijun Zhu
Mesaconitine (MA) and hypaconitine (HA) are the main bioactive/toxic alkaloids of Aconitum carmichaelii Debx, and MDR1 , BCRP and MRP2 are involved in their efflux in vitro . This study aimed to explore the effects of Mdr1a, Bcrp and Mrp2 on the efficacy/toxicity of MA and HA by using efflux transporter gene knockout mouse models. The analgesic and anti-inflammatory effects, neurotoxicity/cardiotoxicity, and pharmacokinetic profiles of MA and HA were studied. Compared to wild-type mice, the analgesic effects of MA or HA were significantly enhanced in Mdr1a ‐ −/− , Bcrp1 −/− and Mrp2 −/− mice, and the anti-inflammatory effects notably increased in Bcrp1 −/− and Mrp2 −/− mice. Compared to wild-type mice, Mdr1a −/− , Bcrp1 −/− and Mrp2 −/− mice suffered from severe karyopyknosis and edema in the brain after MA or HA treatment. Meanwhile, significant arrhythmia appeared, and the heart rate and RR-interval were greatly altered in Mdr1a −/− , Bcrp1 −/− and Mrp2 −/− mice. Additionally, obvious disorder of cardiomyocytes were observed, and the CK and cTnT (indicators of heart injury) levels were greatly enhanced in efflux transporter gene knockout mice. The brain levels of MA and HA were markedly increased in Mdr1a −/− , Bcrp1 −/− and Mrp2 −/− mice, and the heart levels of MA and HA enhanced greatly in Mdr1a −/− mice. The MRT 0-t values of MA and HA were remarkably enhanced in most efflux transporter gene knockout mice. In conclusion, Mdr1a, Bcrp and Mrp2 were all involved in regulating the efficacy/toxicity of MA and HA by altering their tissue accumulation and in vivo residence. Among the three efflux transporters, Mdr1a had a superior regulatory effect.
研究领域:
药理学
·
毒理学
·
药代动力学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PHARMAZIE
·
2018
·Vol. 73
·期 9
·503-507
·
IF 1.016
Liu Yixian,Wang Yafeng,Peng Youmei,Liu Bingjie,Ma Fang,Jiang Jinhua,Wang Qingduan,Chang Junbiao
The purpose of the present study was to dig into recent studies designed to characterize the impacts of 2'-deoxy-2'-β-fluoro-4'-azidocytidine (FNC) on P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). Specifically,
the modulation effects of FNC on P-gp, MRP2 and BCRP protein expressions were assessed by western blot methods. 5 (and 6)-Carboxy-2',7'-dichloroflourescein (CDF) and BODIPY-prazosin were used to provide indications of alterations of MRP2 and BCRP activities. The effects of P-gp, MRP2 and BCRP
on FNC were evaluated in the in situ single-pass intestinal perfusion model. The results showed that FNC at higher concentrations and with longer incubation times can upregulate the protein expression of P-gp, MRP2 and BCRP in Caco-2 cells. The upregulated proteins were also functionally
active, as revealed by a lower degree of CDF and BODIPY-prazosin uptake by the cell monolayers. The intestinal absorptive coefficient (Peff) was observed to significantly increase with the inhibitors of P-gp, MRP2 and BCRP. These results suggested that FNC could modulate the expressions and
functions of P-gp, MRP2 and BCRP, while P-gp, MRP2 and BCRP were involved in the efflux transport of FNC. The inductive effects of FNC on P-gp, MRP2 and BCRP suggested the possibility of FNC to contribute to the inter- and intra-individual variability of itself, as well as to alter the absorption
of other drugs that may be administered concomitantly.
研究领域:
药理学
·
分子生物学
·
药物代谢动力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2018
·
IF 2.064
Renjie Xu,Yichu Yuan,Jia Qi,Jia Zhou,Xiaowen Guo,Jian Zhang,Ruanjuan Zhan
Loganin, iridoid glycosides, is the main bioactive ingredients in the plant Strychnos nux-vomica L. and demonstrates various pharmacological effects, though poor oral bioavailability in rats. In this study, the intestinal absorption mechanism of loganin was investigated using the human intestinal Caco-2 cell monolayer model in both the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) direction; additionally, transport characteristics were systematically investigated at different concentrations, pHs, temperatures, and potential transporters. The absorption permeability (AB) of loganin, which ranged from 12.17 to 14.78 × 10−6cm/s, was high at four tested concentrations (5, 20, 40, and 80μM), while the major permeation mechanism of loganin was found to be passive diffusion with active efflux mediated by multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP). In addition, it was found that loganin was not the substrate of efflux transporter P-glycoprotein (P-gp) since the selective inhibitor (verapamil) of the efflux transporter exhibited little effects on the transport of loganin in the human intestinal Caco-2 cells. Meanwhile, transport from the apical to the basolateral side increased 2.09-fold after addition of a MRP inhibitor and 2.32-fold after addition of a BCRP inhibitor. In summary, our results clearly demonstrate, for the first time, a good permeability of loganin in the human intestinal Caco-2 cell model and elucidate, in detail, the intestinal absorption mechanism and the effects of transporters on iridoid glycosides compounds.
研究领域:
药理学
·
生物医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2026
·
IF 3.6
Zijin Lin,Runze Wu,Yiting Yang,Mingrui Ji,Xiaodong Liu,Li Liu,Hanyu Yang
Patients with liver failure often suffer from hepatic retinopathy, partly due to the blood-retina barrier (BRB) impairment. BRB includes the inner BRB formed by retinal microvascular endothelial cells (RMECs) and the outer BRB formed by retinal pigment epithelial cells (RPECs). Breast cancer resistance protein (BCRP), highly expressed in the inner BRB, regulates retinal homeostasis. To investigate the effects of liver failure on retina BCRP function and expression, we used bile duct ligation (BDL) rats as an animal model, and the BCRP function and BRB integrity were evaluated via retinal prazosin/sulfasalazine distribution and FITC-dextran permeability using total 18 BDL and 18 Sham rats (n=6 per group), respectively. The results demonstrated that BDL significantly downregulated retina BCRP expression (decrease 1.7 fold of Sham rats) and function without affecting BRB permeability, alongside 50-75% reductions in JNK and p-JNK expression, as well as 30% increases in reactive oxygen species (ROS) levels and 2-folds elevations in p-ERK1/2 expression. The primarily cultured rat RMECs were used to investigate the mechanism of BCRP expression impairment by BDL. In vitro , NH 4 Cl significantly downregulated the expression of BCRP, JNK, and p-JNK protein, which were attenuated by JNK activator Metformin. Bilirubin could also decrease BCRP expression, accompanied by increased levels of ROS and p-ERK1/2. N-acetyl-L-cysteine and U0126 attenuated the bilirubin- or H 2 O 2 -induced downregulation of BCRP protein. Confirming in vivo , bilirubin and ammonium acetate recapitulated BCRP suppression via ROS-ERK1/2 and JNK pathways, respectively (n=6 per group). Summary, BDL downregulated the expression and function of BCRP in rat retina, partly due to increases in levels of both ammonia and bilirubin. Ammonia impaired BCRP expression by inactivating the JNK pathway, while bilirubin suppressed BCRP expression by activating the ROS-ERK1/2 pathway. Significance Statement BDL-induced ammonia and bilirubin accumulation downregulated retinal BCRP expression and function. Ammonia impaired the expression of BCRP by inactivating the JNK pathway, while bilirubin suppressed BCRP expression through activating the ROS-ERK1/2 pathway.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 21
·13261
·
IF 6.208
Tsz Cheung Chong,Iris L. K. Wong,Jiahua Cui,Man Chun Law,Xuezhen Zhu,Xuesen Hu,Jason W. Y. Kan,Clare S. W. Yan,Tak Hang Chan,Larry M. C. Chow
Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimerAc15(Az8)2was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC50for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed thatAc15(Az8)2restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a transport substrate of BCRP and showed a non-competitive relationship with DOX in binding to BCRP. A pharmacokinetic study revealed that I.P. administration of 45 mg/kg ofAc15(Az8)2resulted in plasma concentration above its EC50(72 nM) for longer than 24 h. It increased the AUC of topotecan by 2-fold. In an in vivo model of BCRP-overexpressing S1M180 xenograft in Balb/c nude mice, it significantly reversed BCRP-mediated topotecan resistance and inhibited tumor growth by 40% with no serious body weight loss or death incidence. Moreover, it also increased the topotecan level in the S1M180 xenograft by 2-fold. Our results suggest thatAc15(Az8)2is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers.Keywords:multidrug resistance;breast cancer resistance protein;BCRP;ABCG2;flavonoid dimers
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2024
·
IF 3.3
Mangmang Feng,Xiaxia Fan,Jiangying Shi,Shuhua Shan,Songtao Li,Shuiling He,Man Ding,Zhuoyu Li
BACKGROUND Quinoa contains far more nutrients than any traditional grain crop. It is known that terpenoids in quinoa have anti-inflammatory and antitumor effects, but their role in reversing drug resistance remains unclear. RESULTS Our previous studies showed that quinoa-derived terpenoid compounds (QBT) can inhibit the occurrence and development of colon cancer. This study further indicates that QBT markedly reverse drug resistance of colon cancer. The results showed that QBT combined with 5-fluorouracil (5-Fu) treatment significantly enhanced the chemotherapy sensitivity of HCT-8/Fu, compared with 5-Fu treatment alone. Moreover, we found that QBT significantly reduced the expression of drug-resistant proteins (P-gp, MRP1, BCRP), and increased the accumulation of chemotherapy drugs. Taking P-gp as the target for biogenesis prediction analysis, results showed that upregulation of miR-495-3p enhanced the chemosensitivity of drug-resistant HCT-8/Fu cells. Besides, the results showed that miR-495-3p was abnormally methylated in HCT-8/Fu compared with HCT-8 colon cancer cells. The expression of methyltransferases DNMT1, DNMT3a and DNMT3b was abnormal. After QBT treatment, the expression level of methyltransferases returned to normal. In addition, the QBT + 5Fu group showed inhibition of tumors in nude mice. CONCLUSION QBT treatment downregulated the expression of drug-resistant protein P-gp by inhibiting the methylation of miR-495-3p, and enhanced the accumulation of 5-Fu in vivo , which in turn reversed its chemoresistance. This suggests that QBT has potential ability as a new drug-resistance reversal agent in colorectal cancer. © 2024 Society of Chemical Industry.
研究领域:
癌症生物学
·
药理学
·
分子生物学
·
营养科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmacology Research & Perspectives
·
2022
·Vol. 10
·期 1
·e00928
·
IF 2.963
Siyuan Cao,Min Zhang,Minyan Yuan,Dan Yang,Mei Zhao,Shuo Zhang,Pengjiao Wang,Rongping Zhang,Xiuli Gao
The bioavailability of drugs is often related to intestinal metabolism and transport mechanisms. In previous studies, pharmaceutical excipients were recognized as inert substances in clinical safety evaluations. However, a large number of studies have shown that pharmaceutical excipients regulate the metabolism and transport of drugs in the body and improve the bioavailability. The pharmaceutical excipient polyethylene glycol 400 (PEG400) as a good solubilizer and surfactant has the potential to improve the bioavailability of drugs. The combined action of UDP-glucuronosyltransferases (UGTs) and efflux transport proteins is responsible for the intestinal disposition and poor bioavailability of baicalein. Our aim is to study the effect of PEG400 on the absorption of baicalein on the Caco-2 monolayer, and confirm the interaction of PEG400 with UGTs (UGT1A8 and UGT1A9) and efflux transports. We initially found that baicalein in the Caco-2 monolayer would be metabolized into glucuronide conjugates BG and B6G under the action of UGT1A8 and UGT1A9 on the endoplasmic reticulum membrane, and then mainly excreted to different sides by acting of MRP and BCRP. The addition of PEG400 significantly accelerated the metabolism of B in Caco-2 cells and increased the penetration of BG and B6G. Furthermore, PEG400 also significantly decreased the efflux ratio of BG and B6G, which was the evidence of the interaction with the efflux transporters. In the in vitro intestinal microsome regeneration system, low concentration PEG400 decreased the K m value of UGT1A8 and UGT1A9 (key enzymes that mediate the production of BG and B6G); high concentration PEG400 enhanced the V max value of UGT1A8 and UGT1A9. In conclusion, our results determined that PEG400 interacted with some UGTs and efflux transporters, which were the main factors affecting the absorption of baicalein.
研究领域:
药学
·
药理学
·
药物代谢
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 42
·期 11
·1942-1950
·
IF 6.15
Wu Tong,Sheng Yun,Qin Yuan-yuan,Kong Wei-min,Jin Meng-meng,Yang Han-yu,Zheng Xiao-ke,Dai Chang,Liu Ming,Liu Xiao-dong,Liu Li
Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are co-located at blood–brain barrier (BBB) cells, preventing their substrates from entering brain. Accumulating evidence demonstrates that liver failure impairs P-gp and BCRP expression and function in the brain. In the current study, we investigated how liver failure influenced the expression and function of brain BCRP and P-gp in rats subjected to bile duct ligation (BDL). The function of BCRP, P-gp and BBB integrity was assessed using distribution of prazosin, rhodamine 123 and fluorescein, respectively. We showed that BDL significantly decreased BCRP function, but increased P-gp function without affecting BBB integrity. Furthermore, we found that BDL significantly downregulated the expression of membrane BCRP and upregulated the expression of membrane P-gp protein in the cortex and hippocampus. In human cerebral microvascular endothelial cells, NH 4 Cl plus unconjugated bilirubin significantly decreased BCRP function and expression of membrane BCRP protein, but upregulated P-gp function and expression of membrane P-gp protein. The decreased expression of membrane BCRP protein was linked to the decreased expression of membrane radixin protein, while the increased expression of membrane P-gp protein was related to the increased location of membrane ezrin protein. Silencing ezrin impaired membrane location of P-gp, whereas silencing radixin impaired membrane location of BCRP protein. BDL rats showed the increased expression of membrane ezrin protein and decreased expression of membrane radixin protein in the brain. We conclude that BDL causes opposite effects on the expression and function of brain BCRP and P-gp, attributing to the altered expression of membrane radixin and ezrin protein, respectively, due to hyperbilirubinemia and hyperammonemia.
研究领域:
药理学
·
神经科学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 12
·6468
·
IF 4.9
Yuying Li,Wei Yan,Yu Qin,Liwei Zhang,Sheng Xiao
Chemotherapy resistance in cancer is an essential factor leading to high mortality rates. Tumor multidrug resistance arises as a result of the autophagy process. Our previous study found that compound 1-nitro-2 acyl anthraquinone-leucine (C2) exhibited excellent anti-colorectal cancer (CRC) activity involving autophagy and apoptosis-related proteins, whereas its underlying mechanism remains unclear. A notable aspect of this study is how C2 overcomes the multidrug susceptibility of HCT116/L-OHP, a colon cancer cell line that is resistant to both in vitro and in vivo oxaliplatin (trans-/-diaminocyclohexane oxalatoplatinum; L-OHP). In a xenograft tumor mouse model, we discovered that the mixture of C2 and L-OHP reversed the resistance of HCT116/L-OHP cells to L-OHP and inhibited tumor growth; furthermore, C2 down-regulated the gene expression levels ofP-gpandBCRPand decreasedP-gp’sdrug efflux activity. It is important to note that while C2 re-sensitized the HCT116/L-OHP cells to L-OHP for apoptosis, it also triggered a protective autophagic pathway. The expression levels of cleaved caspase-3 and Beclin 1 steadily rose. Expression of PI3K, phosphorylated AKT, and mTOR were decreased, while p53 increased. We demonstrated that the anthraquinone derivative C2 acts as an L-OHP sensitizer and reverses resistance to L-OHP in HCT116/L-OHP cells. It suggests that C2 can induce autophagy in HCT116/L-OHP cells by mediating p53 and the PI3K/AKT/mTOR signaling pathway.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2021
·Vol. 69
·期 11
·1054-1060
·
IF 1.645
Yuqin Zhou,Weitong Hu,Xiangli Zhang,Yi Wang,Wenya Zhuang,Fengzhi Li,Qingyong Li
In the evaluation of the druggability of candidate compounds, it was vital to predict the oral bioavailability of compounds from apparent permeability (Papp) across Caco-2 cell-culture model of intestinal epithelium cultured on commercial transwell plate inserts. The study was to investigate the transport characteristics and permeability of FL118 (10, 11-Methylenedioxy-20(S)-camptothecin) derivatives 7-Q6 (7-(4-Ethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin) and 7-Q20 (7-(4-Trifluoromethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin). Transport characteristics and permeability of the tested compounds to the small intestine were assessed at different concentrations (0.5, 1 µM) via Caco-2 cell monolayers model in vitro. Uptake studies based on Caco-2 cells, including temperatures, concentrations, and the influence of efflux transporters, were combined to confirm the transport characteristics of the tested compounds. Furthermore, cytotoxicity results showed that the concentrations used in the experiments were non-toxic and harmless to cells. In addition, The Papp of 7-Q6 was (3.69 ± 1.07) × 10−6 cm/s with efflux ratio (ER) 0.98, while the Papp of 7-Q20 was (7.78 ± 0.89) × 10−6 cm/s with ER 1.05 for apical-to-basolateral (AP→BL) at 0.5 µM, suggesting that 7-Q20 might possess higher oral bioavailability in vivo. Furthermore, P-glycoprotein (P-gp) was proved to slightly affect the accumulations of 7-Q20, while the absorption of 7-Q6 was irrelevant with P-gp and breast cancer resistant protein (BCRP) based on the cellular uptake assays. Accordingly, 7-Q6 was completely absorbed by passive diffusion, and 7-Q20 was mainly dependent on passive diffusion with being effluxed by P-gp slightly. Meanwhile, both 7-Q6 and 7-Q20 were potential antitumor drugs that might exhibit high oral bioavailability in the body.
研究领域:
药理学
·
药物递送
·
细胞生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2024
·Vol. 52
·期 11
·1332-1344
·
IF 4.4
Yuqing Wang,Jun Luo,Mengru Bai,Zhiyuan Ma,Ying Xu,Dan Liu,Huidi Jiang,Shenglin Ma,Shirong Zhang
Antifolates are important for chemotherapy in non–small cell lung cancer (NSCLC). They mainly rely on reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) to enter cells. PCFT is supposed to be the dominant transporter of the two in tumors, as it operates optimally at acidic pH and has limited transport activity at physiological pH, whereas RFC operates optimally at neutral pH. In this study, we found RFC showed a slightly pH-dependent uptake of antifolates, with similar affinity values at pH 7.4 and 6.5. PCFT showed a highly pH-dependent uptake of antifolates, with an optimum pH of 6.0 for pemetrexed and 5.5 for methotrexate. The Michaelis-Menten constant (Km) value of PCFT for pemetrexed at pH 7.4 was more than 10 times higher than that at pH 6.5. Interestingly, we found that antifolate accumulations mediated by PCFT at acidic pH were significantly affected by the efflux transporter, breast cancer resistance protein (BCRP). The highest pemetrexed concentration was observed at pH 7.0–7.4 after a 60-minute accumulation in PCFT-expressing cells, which was further evidenced by the cytotoxicity of pemetrexed, with the IC50 value of pemetrexed at pH 7.4 being one-third of that at pH 6.5. In addition, the in vivo study indicated that increasing PCFT and RFC expression significantly enhanced the antitumor efficacy of pemetrexed despite the high expression of BCRP. These results suggest that both RFC and PCFT are important for antifolates accumulation in NSCLC, although there is an acidic microenvironment and high BCRP expression in tumors.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
CANCER CHEMOTHERAPY AND PHARMACOLOGY
·
2019
·Vol. 84
·期 3
·527-537
·
IF 3.008
Weng Qi,Zhou Leilei,Xia Lihua,Zheng Yixin,Zhang Xiangli,Li Fengzhi,Li Qingyong
Purpose Recent researches are attempting to verify that the 3D cell models can provide a gap bridge between in vitro and in vivo for anticancer drug evaluations. The aim of this study was to continue the development of novel in vitro 3D cell models and the investigation of the cellular uptake mechanism of camptothecin (CPT) and its derivatives [FL118 (10,11-methylenedioxy-20( S )-camptothecin), 9-Q20 (9- p -trifluoromethylphenyl-10,11-methylenedioxy-20( S )-camptothecin)] in 2D and 3D cell models. Methods The 3D cell models were established using ultralow attachment 96-well plates. The cytotoxicity of CPT, FL118, and 9-Q20 was evaluated by MTT method. The effects of compound concentration, incubation time, temperature, and transporter inhibitors on the cellular uptake of CPT, FL118, and 9-Q20 were examined in 2D and 3D cell models. Results The cytotoxicity of CPT, FL118, and 9-Q20 was lower in 3D cell models than 2D cell models. In 2D Caco-2 cell model, the uptake rate of CPT, FL118, and 9-Q20 was faster during the early time of incubation. In 3D Caco-2 cell model, the uptake capacity of CPT, FL118, and 9-Q20 was significantly improved over time. In 3D Caco-2 cell model, Verapamil (P-gp inhibitor) and Gefitinib (BCRP inhibitor) more significantly increased the uptake of CPT and 9-Q20. In contrast, P-gp and BCRP did not affect the accumulation of FL118 in 2D and 3D Caco-2 cell models. The accumulation of CPT, FL118, and 9-Q20 was greater in HepG2 cells than HCT116 cells. Conclusion The 3D cell models provided more potency information on the process of cellular uptake of CPT, FL118, and 9-Q20, which more objectively reflected the drug sensitivity and drug resistance in vivo compared with the 2D cell models.
研究领域:
药理学
·
肿瘤学
·
细胞生物学
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）