Cell Reports Physical Science
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2026
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IF 6.9
Dian Jiao,Tao Wang,Yinghou Wang,Zhengdi Ma,Mingjia Sun,Chen Meng,Weihua Chen,Yaqi Wang,Yanxin Li,Yaru Song,Xinnan Hou,Zhong Wen,Jingdong Xiao,Zhonggui He,Tianhong Zhang,Jin Sun,Zhenbao Li,Qikun Jiang
Albumin-based drug-delivery systems garner attention due to their inherent biocompatibility and tumor-targeting potential. However, they are limited by weak human serum albumin (HSA) affinity for drugs like camptothecin (CPT). To address this, we synthesize five CPT prodrug derivatives (CPT-SA-C6–C14) with tunable aliphatic alcohol chains as HSA-binding motifs and a succinic acid linker for carboxylesterase (CES1/CES2)-mediated cascade activation. CPT-SA-C10, C12, and C14 achieve ultrahigh drug loading (>30%) in albumin nanoparticles (ANPs) via enhanced HSA affinity. Aliphatic chain length shows an inverted V-shaped correlation with both HSA-binding affinity and CES1-catalyzed hydrolysis. The resulting intermediate is hydrolyzed by CES2 to release CPT. CPT-SA-C12 ANPs exhibit the highest albumin affinity and fastest enzymatic conversion, yielding superior therapeutic efficacy and favorable tolerability. This work elucidates the structure-activity relationship of albumin-bound prodrugs and advances the design of CES-responsive nanomedicines.
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Xiaoting Luo,Feifei Lu,Zhiyue Yin,Zhiyun Zhou,Zhongmin Wang,Hongjian Zhang
Carboxylesterase 1 (CES1) is a hydrolytic enzyme that plays an important role in the activation or deactivation of many therapeutic agents, thus affecting their pharmacokinetic and pharmacodynamic outcomes. Using rat liver S9 as an enzyme source and enalapril as a CES1 substrate, the present study examined effects of a number of flavonoids on the formation of enalaprilat (the active form of enalapril) produced by CES1-mediated hydrolysis. While a majority of flavonoids tested showed inhibition on CES1, an unexpected hormetic effect was observed for epigallocatechin (EGC) and epigallocatechin gallate (EGCG), i.e., stimulatory effect at low concentrations and enzyme inhibition at high concentrations. Further experiments revealed that oxidative stress caused by hydrogen peroxide, arachidonic acid plus iron, and oxidized low density lipoproteins (oxLOL) reduced CES1 activity in rat liver S9 and the loss of CES1 enzyme activity could be rescued largely by EGC or EGCG. In contrast, such effects were minimal in human liver S9, probably due to the presence of a higher ratio of reduced vs oxidized forms of glutathione . The above findings suggest that the polyphenolic nature of EGC or EGCG might be responsible for rescuing CES1 activity under oxidative stress. Because of the importance of CES1 in drug activation or deactivation and rat liver S9 as a versatile in vitro system used for drug metabolism studies and drug safety assessment , caution should be exercised to avoid potential biases for data interpretation and decision making when CES1 activity in rat liver S9 is evaluated with dependency on experimental conditions.
研究领域:
药理学
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毒理学
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生物化学
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药物代谢
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酶学
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PubMed
高影响因子
TOXICOLOGY IN VITRO
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2024
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IF 2.6
Jia-hong Liang,Xiao-lei Yi,Jia-min Gong,Zuo Du
Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.
研究领域:
药理学
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临床药理学
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药物代谢
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Jiang Huan-guo,Zhan Zhi-kun,Tian Ling-min,Chen Yu-lian,Cai Mei-qun,Ge Guang-bo,Chen Xin,Wei Chuan-liang,Tang Lan
Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI’s lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg − 1 ·d − 1 , i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα − / − ) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (−183/−165 bp) and CES2 (−1870/−1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI’s lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.
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PubMed
高影响因子
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