JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Xingyu Gao,Zixia Hu,Yang Wang,Guode Zhao,Yan Shen,Hao Zhou,Yufen Liao,Weiwei Li,Ying Peng,Jiang Zheng
Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity. In rat liver microsomal incubations fortified with glutathione or N-acetylcysteine, one oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetylcysteine conjugate (M3) were detected after exposure to GRM. The corresponding conjugates were detected in the bile and urine of rats after GRM administration. CYP3A was the main enzyme mediating the metabolic activation of GRM. The detected GSH and NAC conjugates suggest that GRM was metabolized to a quinone imine intermediate. Both GRM and M1 showed significant toxicity to rat primary hepatocytes.
研究领域:
毒理学
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药理学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
IF 5.4
Tingmin Ye,Chunping Tang,Dandan Yang,Qing Zhang,Yufen Liao,Jie Dai,Hong Tang,Changqiang Ke,Ying Peng,Yang Ye,Weiwei Li,Jiang Zheng
Bavachin (BVC), a flavonoid, is found in Psoraleae fructus (PF) which has been reported to induce various adverse effects, particularly hepatotoxicity, such as increases of serum alanine transaminase and aspartate transaminase in mice given BVC. However, the mechanisms underlying its hepatotoxicity remain unclear. During the incubation of mouse microsomes with BVC in the presence of glutathione (GSH) or N -acetylcysteine (NAC), one oxidative metabolite (M1), one GSH conjugate (M2), and one NAC conjugate (M3) were observed. M1 was successfully synthesized by selective oxidation of BVC. Similar microsomal incubations of synthetic M1 offered M2 and M3. Following oral administration of BVC, the presence of biliary M2 and urinary M3 was observed in mice given BVC. CYP3A identified as the major enzyme was involved in the metabolic activation of BVC. The metabolic activation of BVC involved hydroxylation of BVC and sequential oxidation of the hydroxylation product to the corresponding o -quinone derivative. BVC treatment resulted in significant cytotoxicity in cultured mouse primary hepatocytes, and pretreatment with 1-aminobenzotriazole and ketoconazole decreased the susceptibility of hepatocytes to the cytotoxicity of BVC. Oral administration of PF extract resulted in a quick decline in hepatic GSH, along with the detection of GSH conjugate M2, in mice. BVC, a principal component of PF, was also found to deplete hepatic GSH in mice over a brief period. This evidence suggests that metabolic activation of BVC leads to depletion of GSH in vivo and that BVC contributes to the depletion of hepatic GSH caused by PF extract.
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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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2021
·Vol. 49
·期 5
·369-378
·
IF 3.922
Wushuang Zeng,Lanlan Gui,Xianwen Tan,Pingping Zhu,Yiting Hu,Qingliang Wu,Xuejing Li,Lian Yang,Wei Jia,Changxiao Liu,Ke Lan
Deoxycholic acid (DCA, 3α, 12α-dihydroxy-5β-cholan-24-oic acid) is the major circulating secondary bile acid, which is synthesized by gut flora in the lower gut and selectively oxidized by CYP3A into tertiary metabolites, including 1β,3α,12α-trihydroxy-5β-cholan-24-oic acid (DCA-1β-ol) and 3α,5β,12α-trihydroxy-5β-cholan-24-oic acid (DCA-5β-ol) in humans. Since DCA has the similar exogenous nature and disposition mechanisms as xenobiotics, this work aimed to investigate whether the tertiary oxidations of DCA are predictive of in vivo CYP3A activities in beagle dogs. In vitro metabolism of midazolam (MDZ) and DCA in recombinant canine CYP1A1, 1A2, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 enzymes clarified that CYP3A12 was primarily responsible for either the oxidation elimination of MDZ or the regioselective oxidation metabolism of DCA into DCA-1β-ol and DCA-5β-ol in dog liver microsomes. Six male dogs completed the CYP3A intervention studies including phases of baseline, inhibition (ketoconazole treatments), recovery, and induction (rifampicin treatments). The oral MDZ clearance after a single dose was determined on the last day of the baseline, inhibition, and induction phases, and subjected to correlation analysis with the tertiary oxidation ratios of DCA detected in serum and urine samples. The results confirmed that the predosing serum ratios of DCA oxidation, DCA-5β-ol/DCA, and DCA-1β-ol/DCA were significantly and positively correlated both intraindividually and interindividually with oral MDZ clearance. It was therefore concluded that the tertiary oxidation of DCA is predictive of CYP3A activity in beagle dogs. Clinical transitional studies following the preclinical evidence are promising to provide novel biomarkers of the enterohepatic CYP3A activities.
研究领域:
药理学
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生物化学
·
临床医学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2014
·Vol. 42
·期 5
·839-843
·
IF 3.334
Ke Li,Sylvia Zhao,Lingling Zhang,Xiaoyun Wu,Pan Shu,Yang Wang,Hao Feng,Zheming Gu,Helen Han Hsu
It has been proposed that in humans 4β-hydroxycholesterol is formed mainly by CYP3A-catalyzed metabolism of cholesterol and thus may serve as an endogenous marker for CYP3A activity. The cynomolgus monkey is widely used as one of the nonrodent preclinical safety species in pharmaceutical research. In the current study, the potential application of 4β-hydroxycholesterol as an endogenous biomarker of CYP3A in response to drug treatment was evaluated in cynomolgus monkeys. Following multiple oral administration of rifampicin (a known CYP3A inducer) at 15 mg/kg/d in cynomolgus monkeys, the mean serum 4β-hydroxycholesterol levels increased 4-fold from the baseline of 55.3 ± 21.7 to 221 ± 53.4 ng/ml. The mean concentration ratios of 4β-hydroxycholesterol to cholesterol increased 5-fold. The data suggest that 4β-hydroxycholesterol formation from cholesterol metabolism was induced by rifampicin treatment in monkeys. This observation correlated with the metabolism of midazolam (a probe substrate of CYP3A activity) monitored in the same study. The serum exposure (area under the curve) of midazolam was markedly decreased by ∼95%, confirming the induction of CYP3A catalytic activity by rifampicin treatment in monkeys. The formation of 4β-hydroxycholesterol from cholesterol was specifically mediated by recombinant cynomolgus CYP3A8 and CYP3A5. The Km values of CYP3A8 and CYP3A5 for 4β-hydroxycholesterol formation from cholesterol were 204 and 104 μM, respectively, and Vmax values were 0.600 and 0.310 pg/pmol/min, respectively. The results suggest that 4β-hydroxycholesterol can be used as an endogenous biomarker to identify strong CYP3A inducers in cynomolgus monkeys, which may help to evaluate drug-drug interaction potential of drug candidates in preclinical settings.
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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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Guang-rong Lu,Rui-zhen Wang,Xin-yu Zhao,Jun-er Xu,Cheng-ke Huang,Wei Sun,Rui-jie Chen,Zhe Wang
Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC (0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC (0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions.
研究领域:
药理学
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肿瘤学
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临床医学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2020
·
IF 3.723
Wei Zhang,Jingyan Guo,Dongmei Wang,Shumeng Ren,Huiming Hua,Toshio Morikawa,Yingni Pan,Xiaoqiu Liu
Evodiae Fructus (EF), the dried nearly mature scented fruit of Tetradium ruticarpum (A.Juss.) T.G.Hartley, was typically used to treat headache, abdominal pain, hernias, and menorrhagia for thousands of years. It had been reported to be a mild toxic herb through metabolic activation mainly by CYP3A but was barely explained from pharmacokinetic interaction. The aim of the study was to investigate the role of CYP3A inducer/inhibitor in pharmacokinetics of five alkaloids (evodiamine (EVOD), rutaecarpine (RUTA), 1-methyl-2-undecyl-4(1 H )-quinolone (MUDQ), 1-methyl-2-nonyl-4(1 H )-quinolone (MNNQ) and evocarpine (EVOC)) associated with hepatotoxicity of EF in Sprague Dawley (SD) rats. The results demonstrated that the metabolism of the five alkaloids of EF were inhibited in presence of CYP3A inhibitor whereas the metabolism of the five alkaloids of EF were promoted in presence of CYP3A inducer . Therefore, the dose is required attention when EF is taken in conjunction with CYP3A inducer as there is an enhancement in drug metabolism, which might lead to toxicity.
研究领域:
中药学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
AQUACULTURE INTERNATIONAL
·
2025
·Vol. 33
·期 3
·1-18
·
IF 2.4
Kong Lingnan,Abulizi Abudula,Cong Jingjing,Meng Weihan,Chang Yaqing,Sun Zhihui
The cytochrome P4503A ( CYP3A ) subfamily has been well characterized in vertebrates, where it plays a pivotal role in xenobiotic detoxification and the regulation of steroid hormone levels. However, their molecular features and functions in invertebrates remain poorly understood. The sea cucumber ( Apostichopus japonicus ) is not only a commercially significant mariculture species but also an excellent model for studying organ development and evolutionary biology. In this study, we identified seven CYP3A genes in A. japonicus using gonadal transcriptomic data. These genes exhibited ubiquitous expression across adult tissues, with significantly higher levels in ovarian tissues compared to testes tissues. Protein sequence analysis revealed that the catalytic residues Ala 306 -Thr 310 -Cys 437 , which are critical for aromatase activity, are highly conserved. This suggests that CYP3A proteins may mediate aromatization-like reactions similar to CYP19A in vertebrates. Additionally, dietary administration of the aromatase inhibitor letrozole led to histological changes in the testes and a reduction in the diameter of large oocytes in the ovaries. These findings provide valuable insights into the molecular mechanisms underlying gonadal development in sea cucumbers and lay the groundwork for future research on the artificial induction of sex reversal in echinoderms.
研究领域:
分子生物学
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海洋生物学
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进化生物学
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产品关联
DOI
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2023
·Vol. 51
·期 11
·1515-1526
·
IF 3.9
Xiaowen Wang,Yiqun Yu,Hongrui Liu,Fengjiao Bu,Chunying Shen,Qingfeng He,Xiao Zhu,Pin Jiang,Bing Han,Xiaoqiang Xiang
Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non–small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug–drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration.
研究领域:
药理学
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临床药学
·
生物医学工程
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DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2018
·
IF 3.432
Li-Long Jiang,Yan Jiang,Dong-Sheng Zhao,Ya-Xi Fan,Qiong Yu,Ping Li,Hui-Jun Li
1,3,8-Trihydroxy-6-methylanthraquinone (emodin), a widely existing natural product in herbal medicines, has been reported to be hepatotoxic, but the exact underlying mechanism is still not fully understood. The objective of the present study was to evaluate the role of CYP3A and glutathione (GSH) in emodin-induced liver injury. Primary human hepatocytes were exposed to emodin with and without addition of CYP3A inducer/inhibitor and GSH synthesis inhibitor. It was found that emodin-mediated cytotoxicity increased when CYP3A was activated and GSH was depleted. Hepatotoxicity induced by emodin in rats by activation/inhibition of CYP3A and depletion of GSH was further investigated. Administration of emodin in combination with l-buthionine sulfoximine (BSO) or dexamethasone (DEX) resulted in aggravated liver injury, whereas pretreatment with ketoconazole (KTZ) suppressed the side effects caused by emodin. In addition, plasma exposure of emodin and its glucuronide metabolite were measured by ultraperformance liquid chromatography triple quadrupole mass spectrometry. Emodin and its glucuronide were lower in BSO-, DEX-, and KTZ-co-treated rats compared with those administered with emodin alone. In conclusion, these mentioned results suggested that CYP3A induction and GSH depletion might be involved in hepatotoxicity induced by emodin. This study may help to understand the risk factors and the mechanism of hepatotoxicity of emodin in humans.
研究领域:
药理学
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毒理学
·
药学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2023
·Vol. 51
·期 12
·1651-1662
·
IF 3.9
Xue Zhang,Jianquan Pan,Xi Ye,Yunna Chen,Lei Wang,Xiangyun Meng,Weidong Chen,Fengling Wang
Reduced enzyme activity in hepatocellular carcinoma (HCC) and poor targeting limit the application of enzyme-activating prodrugs, which is also detrimental to the effective treatment of HCC. Here, we investigated whether accelerated blood clearance (ABC) phenomenon occurs in HCC models following repeated injections of PEGylated liposomes (PEG-L), thus inducing prodrug accumulation and activation in the liver and exerting highly effective and low-toxicity therapeutic effects on HCC. First, PEGylated liposomal cyclophosphamide was prepared by solvent injection and characterized. Importantly, preinjection of PEG-L induced the ABC phenomenon and activation of CYP3A in both HCC rats and HCC mice by studying the effects of repeated injections of PEG-L on pharmacokinetics and tissue distribution. Next, the efficacy and toxicity of repeated injections of PEG-L in HCC mice were examined, and our data indicate that repeated injections are administered in a manner that significantly enhances the antitumor effect compared with controls, with little or no toxicity to other organs. To further reveal the pharmacokinetic mechanism of PEG-L repeated administration for the treatment of HCC, the protein expression of hepatic CYP3A and the concentration of cyclophosphamide in the liver and spleen of HCC mice by inhibiting CYP3A were analyzed. These results revealed that inducing CYP3A to accelerate the rapid conversion of prodrugs that accumulate significantly in the liver is a key mechanism for the treatment of HCC with repeated injections of PEG-L. Collectively, this work taps into the application potential of the ABC phenomenon and provides new insights into the clinical application of PEGylated nanoformulations.
研究领域:
药理学
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肿瘤学
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纳米医学
·
药物递送系统
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DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2024
·
IF 4.8
Sun Chen,Zhang Mingyu,Guan Chunjing,Li Weiwei,Peng Ying,Zheng Jiang
Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N -acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat & human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6’ of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10–400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.
研究领域:
药理学
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毒理学
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药物代谢
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2026
·Vol. 18
·期 6
·718
·
IF 6.9
Kai-Juan Cao,Long Fu,Yu-Chen Sun,Jian Meng,Qin Huang,De-Cheng Deng,Hai-Tang Hu,Zhi-Hui Han,Gang Guo,Xue Zhou,Xiao-Yan Chen
Background/Objectives: Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker (P-CAB) used for the treatment of gastroesophageal reflux disease (GERD). To date, its metabolic pathways and metabolism-related drug–drug interactions (DDIs) in humans remain incompletely elucidated. This study aimed to determine the relative contributions (fm) of cytochrome P450 isoforms to JP-1366 elimination and assess its DDI potential.Methods/Results: In vitro metabolic studies using human liver microsomes (HLMs) revealed that JP-1366 was first metabolized to M1, which subsequently underwent further oxidation, glucuronidation, andN-dealkylation. Mono-oxidation was estimated to contribute more than 46% to the overall metabolic clearance of JP-1366. Reaction phenotyping identified CYP3A as the major enzyme (fm= 96.1%), followed by CYP1A2 (1.49%) and CYP2C9 (2.41%). By integrating in vitro data, clinical pharmacokinetic data and clarithromycin coadministration DDI data, a physiologically based pharmacokinetic (PBPK) model was developed and validated. Simulations predicted significant DDIs with strong CYP3A inhibitor (ketoconazole), with AUC ratios of 3.80. Moderate inhibitors (fluconazole and fluvoxamine) caused mild increases (AUC ratios: 1.14–1.74). Conversely, strong and moderate CYP3A inducers, rifampicin and efavirenz, produced pronounced DDIs, with AUC ratios of 0.22 and 0.50, respectively. Furthermore, simulations predicted that although JP-1366 functions as a CYP enzyme inhibitor, it would not cause clinically meaningful changes in the plasma exposure of corresponding CYP substrate drugs; however, potential interactions with CYP3A substrates still warranted consideration.Conclusions: JP-1366 is predominantly cleared via a CYP3A-dominated metabolic pathway. The PBPK simulations suggest that JP-1366 may be a moderately sensitive CYP3A substrate and a moderate inhibitor of sensitive CYP3A substrates, while its perpetrator DDI risk toward other major CYP pathways appears limited. These findings support caution or monitoring when JP-1366 is co-administered with strong CYP3A modulators or sensitive CYP3A substrates.
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DOI
PubMed
高影响因子
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