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Article ; Online: Han Chinese specific cytochrome P450 polymorphisms and their impact on the metabolism of anti-hypertensive drugs with adrenoreceptor blocking properties.

Qian, Jian-Chang / Cai, Jian-Ping / Hu, Guo-Xin

Expert opinion on drug metabolism & toxicology

2021 Volume 17, Issue 6, Page(s) 707–716

Abstract: ... ...

Abstract	Introduction
MeSH term(s)	Adrenergic Antagonists/pharmacokinetics ; Adrenergic Antagonists/pharmacology ; Antihypertensive Agents/pharmacokinetics ; Antihypertensive Agents/pharmacology ; Asian Continental Ancestry Group/genetics ; Cytochrome P-450 Enzyme System/genetics ; Genotype ; Humans ; Polymorphism, Genetic
Chemical Substances	Adrenergic Antagonists ; Antihypertensive Agents ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2021-05-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2214462-6
ISSN	1744-7607 ; 1742-5255
ISSN (online)	1744-7607
ISSN	1742-5255
DOI	10.1080/17425255.2021.1921147
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Zs.A 6264: Show issues

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Article ; Online: Effect of apatinib on the pharmacokinetics of tramadol and O-desmethyltramadol in rats.

Bao, Su-Su / Tang, Peng-Fei / Gao, Nan-Yong / Xiao, Zhong-Xiang / Qian, Jian-Chang / Zheng, Long / Hu, Guo-Xin / Xu, Huan-Hai

PeerJ

2023 Volume 11, Page(s) e16051

Abstract: Since the combination of anticancer drugs and opioids is very common, apatinib and tramadol are likely to be used in combination clinically. This study evaluated the effects of apatinib on the pharmacokinetics of tramadol and its main metabolite O- ... ...

Abstract	Since the combination of anticancer drugs and opioids is very common, apatinib and tramadol are likely to be used in combination clinically. This study evaluated the effects of apatinib on the pharmacokinetics of tramadol and its main metabolite O-desmethyltramadol in Sprague-Dawley (SD) rats and the inhibitory effects of apatinib on tramadol in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP2D6.1. The samples were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The
MeSH term(s)	Humans ; Rats ; Animals ; Tramadol/pharmacology ; Chromatography, Liquid ; Cytochrome P-450 CYP2D6 ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry ; Microsomes, Liver
Chemical Substances	O-demethyltramadol (2WA8F50C3F) ; Tramadol (39J1LGJ30J) ; apatinib (5S371K6132) ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1)
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2703241-3
ISSN	2167-8359 ; 2167-8359
ISSN (online)	2167-8359
ISSN	2167-8359
DOI	10.7717/peerj.16051
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Article: Genetic variants, haplotype determination, and function of novel alleles of

Zhang, Li-Qun / Li, Xin-Yue / Chen, Lian-Guo / Chen, Zhe / Xu, Ren-Ai / Qian, Jian-Chang / Zhou, Xiao-Yang / Dai, Da-Peng / Hu, Guo-Xin / Cai, Jian-Ping

Heliyon

2024 Volume 10, Issue 7, Page(s) e28952

Abstract: Amino acid variants in protein may result in deleterious effects on enzymatic activity. In this study we investigate the DNA variants on activity ... ...

Abstract	Amino acid variants in protein may result in deleterious effects on enzymatic activity. In this study we investigate the DNA variants on activity of
Language	English
Publishing date	2024-03-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2024.e28952
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Article ; Online: Enzymatic activity on valsartan of 38 CYP2C9 variants from the Chinese population.

Yuan, Ling-Jing / Qian, Jian-Chang / Li, Xiang-Yu / Cui, Ju / Cai, Jian-Ping / Hu, Guo-Xin

Chemico-biological interactions

2022 Volume 353, Page(s) 109799

Abstract: Background and objective: Valsartan is widely used for the treatment of moderate hypertension. However, previous studies have found that efficacy of the valsartan depends on the dose and intake. Cytochrome P450 (CYP) 2C9 metabolizes ∼15% of the clinical ...

Abstract	Background and objective: Valsartan is widely used for the treatment of moderate hypertension. However, previous studies have found that efficacy of the valsartan depends on the dose and intake. Cytochrome P450 (CYP) 2C9 metabolizes ∼15% of the clinical drugs. Genetic polymorphisms of CYP2C9 markedly affect the safety and effectiveness of many drugs, which might lead to adverse reactions and therapeutic failure. Twenty-four novel CYP2C9 variants (36-60) had been previously discovered via gene sequencing in the Han population. Our study aims to evaluate the impact of 38 CYP2C9 variants from the Chinese population on valsartan metabolism compared with CYP2C91 in vitro. Methods:* Wild-type CYP2C91 and other CYP2C9 variants were expressed in Spodoptera frugiperda 21 insect cells. Incubations were performed at 37 °C with 20-2000 μM substrate for 30 min. The metabolite 4-OH valsartan was determined via UPLC-MS/MS. Results:* Among the 38 CYP2C9 variants, the enzymatic activities of most variants were significantly altered compared with the wild-type. Three variants (CYP2C927, 40 and 49) exhibited increased intrinsic clearance values (134-153% relative clearance). However, 12 variants (CYP 8, 13, 16, 19, 33, 36, 42, 43, 45, 52, 54, 58) caused >90% decreases in the relative clearance of valsartan compared to CYP2C91. Conclusions: Our research provides systematic data for evaluating the effects of CYP2C9 variants on valsartan metabolism in the Chinese population. These results will expand our understanding of the impact of CYP2C9 genetic polymorphisms on valsartan metabolism and will contribute to precision medicine.
MeSH term(s)	Asians/genetics ; China ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP2C9/chemistry ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 CYP2C9/metabolism ; Humans ; Kinetics ; Protein Structure, Tertiary ; Tandem Mass Spectrometry ; Valsartan/analysis ; Valsartan/metabolism
Chemical Substances	Valsartan (80M03YXJ7I) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-)
Language	English
Publishing date	2022-01-05
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2022.109799
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Article ; Online: Functional evaluation of CYP2C19 and CYP3A4 gene polymorphism on ibuprofen metabolism.

Yuan, Ling-Jing / Li, Xiang-Yu / Ni, Jin-Huan / Wang, Jing / Xu, Xiao-Yu / Luo, Jian-Chao / Zhou, Qi / Hu, Guo-Xin / Cai, Jian-Ping / Qian, Jian-Chang

Toxicology and applied pharmacology

2023 Volume 475, Page(s) 116653

Abstract: Aim: Ibuprofen is the most commonly used analgesic. CYP polymorphisms are mainly responsible for the differences in drug metabolism among individuals. Variations in the ability of populations to metabolize ibuprofen can lead to drug exposure events. The ...

Abstract	Aim: Ibuprofen is the most commonly used analgesic. CYP polymorphisms are mainly responsible for the differences in drug metabolism among individuals. Variations in the ability of populations to metabolize ibuprofen can lead to drug exposure events. The aim of this study was to evaluate the effects of CYP2C19 and CYP3A4 polymorphisms on ibuprofen metabolism in a Chinese population. Methods: First, 31 CYP2C19 and 12 CYP3A4 microsomal enzymes were identified using an insect expression system. Then, variants were evaluated using a mature incubation system. Moreover, ibuprofen metabolite content was determined via ultra-performance liquid chromatography-tandem mass spectrometry analysis. Finally, kinetic parameters of CYP2C19 and CYP3A4 genotypes were determined via Michaelis-Menten curve fitting. Results: Most variants exhibited significantly altered intrinsic clearance compared to the wild type. In the CYP2C19 metabolic pathway, seven variants exhibited no significant alterations in intrinsic clearance (CL Conclusion: To the best of our knowledge, this is the first study to assess the kinetic characteristics of 31 CYP2C19 and 12 CYP3A4 genotypes on ibuprofen metabolism. However, further studies are needed on poor metabolizers as they are more susceptible to drug exposure. Our findings suggest that the kinetic characteristics in combination with artificial intelligence to predict the toxicity of ibuprofen and reduce any adverse drug reactions.
MeSH term(s)	Humans ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Ibuprofen ; Cytochrome P-450 CYP2C19/genetics ; Artificial Intelligence ; Polymorphism, Genetic
Chemical Substances	Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Ibuprofen (WK2XYI10QM) ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1) ; CYP2C19 protein, human (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55)
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2023.116653
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Article ; Online: Effect of flavonoids and CYP3A4 variants on midostaurin metabolism.

Xu, Ren-Ai / Li, Qing-Qing / Gao, Nan-Yong / Wang, Jing / Li, Xin-Yue / Ye, Feng / Ni, Jin-Huan / Hu, Guo-Xin / Qian, Jian-Chang

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2023 Volume 174, Page(s) 113669

Abstract: The objective of this study was to determine the effect of flavonoids on midostaurin disposition considering co-administration and metabolic enzyme gene polymorphism. Enzymatic incubation assays were performed in vitro, while in vivo experiments were ... ...

Abstract	The objective of this study was to determine the effect of flavonoids on midostaurin disposition considering co-administration and metabolic enzyme gene polymorphism. Enzymatic incubation assays were performed in vitro, while in vivo experiments were conducted in Sprague-Dawley rats. The analytes were determined via UPLC-MS/MS. We found that myricetin was the most potent among the investigated 10 flavonoids in suppressing the metabolism of midostaurin, with an IC
MeSH term(s)	Rats ; Humans ; Animals ; Cytochrome P-450 CYP3A/metabolism ; Rats, Sprague-Dawley ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Flavonoids/pharmacology
Chemical Substances	midostaurin (ID912S5VON) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Flavonoids ; CYP3A4 protein, human (EC 1.14.14.55)
Language	English
Publishing date	2023-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2023.113669
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Article ; Online: A modified nucleoside O6-methyl-2'-deoxyguanosine-5'-triphosphate exhibits anti-glioblastoma activity in a caspase-independent manner.

Wang, Zi-Hui / Li, Jin / Liu, Qian / Qian, Jian-Chang / Li, Qing-Qing / Wang, Qing-Yu / Zeng, Lv-Tao / Li, Si-Jia / Gao, Xin / Pan, Jia-Xin / Gao, Xu-Fan / Wu, Kun / Hu, Guo-Xin / Iwakuma, Tomoo / Cai, Jian-Ping

Pharmacological research

2023 Volume 199, Page(s) 106990

Abstract: Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we ...

Abstract	Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2'-deoxyguanosine-5'-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens.
MeSH term(s)	Humans ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Alkylating/therapeutic use ; Nucleosides/pharmacology ; Nucleosides/therapeutic use ; Caspases ; Cell Line, Tumor ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Nucleotides ; O(6)-Methylguanine-DNA Methyltransferase/metabolism ; O(6)-Methylguanine-DNA Methyltransferase/pharmacology ; O(6)-Methylguanine-DNA Methyltransferase/therapeutic use ; Deoxyguanosine/pharmacology ; Deoxyguanosine/therapeutic use ; DNA ; Drug Resistance, Neoplasm ; Polyphosphates
Chemical Substances	Antineoplastic Agents, Alkylating ; Nucleosides ; Caspases (EC 3.4.22.-) ; triphosphoric acid (NU43IAG5BC) ; Temozolomide (YF1K15M17Y) ; Nucleotides ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63) ; Deoxyguanosine (G9481N71RO) ; DNA (9007-49-2) ; Polyphosphates
Language	English
Publishing date	2023-11-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2023.106990
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Zs.A 721: Show issues

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Article ; Online: MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.

Luo, Wu / Ye, Lin / Hu, Xue-Ting / Wang, Mei-Hong / Wang, Min-Xiu / Jin, Lei-Ming / Xiao, Zhong-Xiang / Qian, Jian-Chang / Wang, Yi / Zuo, Wei / Huang, Li-Jiang / Liang, Guang

Clinical and translational medicine

2022 Volume 12, Issue 3, Page(s) e777

Abstract: Background: Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in ... ...

Abstract	Background: Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. Methods: Wild-type, Md2 Results: Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD-mediated suppression of AMP-activated protein kinase (AMPK). This preservation of AMPK in Md2-deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2-increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. Conclusion: Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1-AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non-inflammatory function of MD2 and evidence for the important role of MD2 in NALFD.
MeSH term(s)	AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Animals ; Diet, High-Fat/adverse effects ; Lipids/adverse effects ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/metabolism ; Protein Serine-Threonine Kinases/genetics
Chemical Substances	Lipids ; Tbk1 protein, mouse (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2022-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.777
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Article ; Online: Dectin-1 plays a deleterious role in high fat diet-induced NAFLD of mice through enhancing macrophage activation.

Wang, Min-Xiu / Luo, Wu / Ye, Lin / Jin, Lei-Ming / Yang, Bin / Zhang, Qian-Hui / Qian, Jian-Chang / Wang, Yi / Zhang, Yi / Liang, Guang

Acta pharmacologica Sinica

2022

Abstract: The innate immune response and inflammation contribute to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Dectin-1 is a pathogen recognition receptor in innate immunity. In this study, we investigated the role of Dectin-1 in the ... ...

Abstract	The innate immune response and inflammation contribute to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Dectin-1 is a pathogen recognition receptor in innate immunity. In this study, we investigated the role of Dectin-1 in the pathogenesis of NAFLD. We first showed that Dectin-1 expression was significantly elevated in liver tissues of patients with NASH. NAFLD was induced in mice by feeding high fat diet (HFD) for 24 weeks. At the end of treatment, mice were sacrificed, and their blood and liver tissues were collected for analyses. We showed HFD feeding also increased liver Dectin-1 levels in mice, associated with macrophage infiltration. Either gene knockout or co-administration of a Dectin-1 antagonist laminarin (150 mg/kg twice a day, ip, from 16
Language	English
Publishing date	2022-06-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/s41401-022-00926-2
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Article ; Online: Functional Measurement of CYP2C9 and CYP3A4 Allelic Polymorphism on Sildenafil Metabolism.

Tang, Peng-Fei / Zheng, Xiang / Hu, Xiao-Xia / Yang, Cheng-Cheng / Chen, Zhe / Qian, Jian-Chang / Cai, Jian-Ping / Hu, Guo-Xin

Drug design, development and therapy

2020 Volume 14, Page(s) 5129–5141

Abstract: Aim: We aimed to systematically examine the effects of enzymatic activity of 38 human : Methods: The recombinant cytochrome P450 alleles protein of : Results: The intrinsic clearance (Vmax/Km) values of most : Conclusion: These findings were ... ...

Abstract	Aim: We aimed to systematically examine the effects of enzymatic activity of 38 human Methods: The recombinant cytochrome P450 alleles protein of Results: The intrinsic clearance (Vmax/Km) values of most Conclusion: These findings were the first evaluation of all these infrequent
MeSH term(s)	Alleles ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 CYP2C9/metabolism ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Humans ; Polymorphism, Genetic/genetics ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sildenafil Citrate/metabolism
Chemical Substances	Recombinant Proteins ; Sildenafil Citrate (BW9B0ZE037) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55)
Language	English
Publishing date	2020-11-24
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S268796
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