Quantitative Proteomics in Translational Absorption, Distribution, Metabolism, and Excretion and Precision Medicine

Ahire, Deepak; Kruger, Laken; Sharma, Sheena; Mettu, Vijaya Saradhi; Basit, Abdul

doi:10.1124/pharmrev.121.000449

Cited by 16 publications

(14 citation statements)

References 227 publications

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“…Absorption, distribution, metabolism, and excretion (ADME) filtration is of great significance to the development of drugs [31,32]. Based on ADME properties, the criteria of "quantitative estimate of drug − likeness ðQEDÞ ≥ 0:2" [33] was applied to sort out active components of Simiao pill.…”

Section: Screening Of Active Components Of Simiao Pill Andmentioning

confidence: 99%

[Retracted] A Network Pharmacology Method Combined with Molecular Docking Verification to Explore the Therapeutic Mechanisms Underlying Simiao Pill Herbal Medicine against Hyperuricemia

Yin

et al. 2023

BioMed Research International

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Objective. Hyperuricemia (HUA) is a common metabolic disease caused by disordered purine metabolism. We aim to reveal the mechanisms underlying the anti-HUA function of Simiao pill and provide therapeutic targets. Methods. Simiao pill-related targets were obtained using Herbal Ingredients’ Targets (HIT), Traditional Chinese Medicine Systems Pharmacology (TCMSP), and Traditional Chinese Medicine Integrated Database (TCMID). HUA-associated targets were retrieved from GeneCards, DisGeNET, and Therapeutic Targets Database (TTD). Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, ggraph and igraph R packages. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfiler. The top 10 core targets were identified through cytoHubba. Molecular docking was conducted using PyMOL and AutoDock high-performance liquid chromatograph (HPLC) analysis was performed to identify effective compounds of Simiao pill. Results. Simiao pill-HUA target network contained 80 targets. The key targets were mainly involved in inflammatory responses. Insulin (INS), tumor necrosis factor (TNF), interleukin-6 (IL6), interleukin 1 beta (IL1B), vascular endothelial growth factor A (VEGFA), leptin (LEP), signal transducer and activator of transcription 3 (STAT3), C-C motif chemokine ligand 2 (CCL2), interleukin-10 (IL10), and toll like receptor 4 (TLR4) were the top 10 targets in the PPI network. GO analysis demonstrated the main implication of the targets in molecular responses, production, and metabolism. KEGG analysis revealed that Simiao pill might mitigate HUA through advanced glycation end-product- (AGE-) receptor for AGE- (RAGE-) and hypoxia-inducible factor-1- (HIF-1-) associated pathways. IL1B, IL6, IL10, TLR4, and TNF were finally determined as the promising targets of Simiao pill treating HUA. Through molecular docking and HPLC analysis, luteolin, quercetin, rutaecarpine, baicalin, and atractylenolide I were the main active compounds. Conclusions. Simiao pill can mitigate HUA by restraining inflammation, mediating AGE-RAGE- and HIF-1-related pathways, and targeting IL1B, IL6, IL10, TLR4, and TNF.

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Section: Screening Of Active Components Of Simiao Pill Andmentioning

confidence: 99%

[Retracted] A Network Pharmacology Method Combined with Molecular Docking Verification to Explore the Therapeutic Mechanisms Underlying Simiao Pill Herbal Medicine against Hyperuricemia

Yin

et al. 2023

BioMed Research International

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“…Here, all groups took advantage of the recent advantages of mass spectrometry-based protein quantification, which enabled highly sensitive, specific, and accurate protein quantification. [8][9][10] However, despite the great value of those data, there is missing information about "minor" DMEs being beyond the scope of most previous investigations, but important for the metabolism of a significant number of drugs used in clinical practice.…”

Section: Articlementioning

confidence: 99%

“…Given the uncertain correlation of gene expression and protein amounts of DMEs, protein data would be preferable. In this regard, highly specific and sensitive mass spectrometric methods for quantitative protein analysis, such as the targeted proteomic approach, are today's methods of choice 8,9 . In contrast to former antibody‐based, semiquantitative methods, such as Western blotting, this approach does not require antibodies, which are not always commercially available and suffer from uncertain specificity due to cross‐reactivity with other proteins.…”

mentioning

confidence: 99%

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Wenzel,

Lapczuk‐Romanska,

Malinowski

et al. 2023

Clin Pharma and Therapeutics

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First pass metabolism by phase I and phase II‐enzymes in the intestine and liver is a major determinant of the oral bioavailability of many drugs. Several studies analyzed expressions of major drug‐metabolizing enzymes (DMEs) such as CYP3A4 and UGT1A1 in the human gut and liver. However, there is still a lack of knowledge regarding other DMEs, i.e. “minor” DMEs, although several clinically relevant drugs are affected by those enzymes. Moreover, there is very limited intra‐subject data on hepatic and intestinal expression levels of minor DMEs. To fill this gap of knowledge, we analyzed gene expression (qRT‐PCR) and protein abundance (targeted proteomics) of 24 clinically relevant DMEs, i.e. carboxylesterases (CES), UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP)‐enzymes. We performed our analysis using jejunum and liver tissue specimens from the same 11 healthy organ donors (8 males, 3 females, aged 19‐60 y). Protein amounts of all investigated DMEs, with the exception of CYP4A11, were detected in human liver samples. CES2, CYP2C18, CYP3A4 and UGT2B17 protein abundance was similar or even higher in the jejunum, and all other DMEs were found in higher amounts in the liver. Significant correlations between gene expression and protein levels were observed only for 2 of 15 jejunal, but 13 of 23 hepatic DMEs. Intestinal and hepatic protein amounts only significantly correlated for CYP3A4 and UGT1A3. Our results demonstrated a notable variability between the individuals, which was even higher in the intestine than in the liver. Our intra‐subject analysis of DMEs in the jejunum and liver from healthy donors may be useful for PBPK‐based modelling and prediction in order to improve efficacy and safety of oral drug therapy.

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“…If REF values are based on DMET quantification in different laboratories, they will likely be confounded by technical variability in protein abundance measurement. The inter-laboratory variability in quantitative proteomics is mainly caused by differences in surrogate peptide-specific characteristics such as solubility, stability, and calibrator quality as well as digestion efficiency (Ahire et al, 2022b). Moreover, inter-day variability in digestion efficiency is also commonly observed (Wegler et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Quantification of Accurate Composition and Total Abundance of Homologous Proteins by Conserved-Plus-Surrogate Peptide Approach: Quantification of UDP Glucuronosyltransferases in Human Tissues

et al. 2022

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Characterization of accurate compositions and total abundance of homologous drugmetabolizing enzymes, such as UDP glucuronosyltransferases (UGTs), is important for predicting the fractional contribution of individual isoforms involved in the metabolism of a drug for applications in physiologically based pharmacokinetic (PBPK) modeling. Conventional targeted proteomics utilizes surrogate peptides, which often results in high technical and interlaboratory variability due to peptide-specific digestion leading to data inconsistencies. To address this problem, we developed a novel universal conserved-plus-surrogate peptide (CPSP) approach for determining the accurate compositions and total or cumulative abundance of homologous UGTs in commercially available pooled human liver microsomes (HLM), human intestinal microsomes (HIM), human kidney microsomes (HKM), and human liver S9 (HLS9) fractions. The relative percent composition of UGT1A and UGT2B isoforms in the human liver was 35:

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Quantitative Proteomics in Translational Absorption, Distribution, Metabolism, and Excretion and Precision Medicine

Cited by 16 publications

References 227 publications

[Retracted] A Network Pharmacology Method Combined with Molecular Docking Verification to Explore the Therapeutic Mechanisms Underlying Simiao Pill Herbal Medicine against Hyperuricemia

[Retracted] A Network Pharmacology Method Combined with Molecular Docking Verification to Explore the Therapeutic Mechanisms Underlying Simiao Pill Herbal Medicine against Hyperuricemia

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Quantification of Accurate Composition and Total Abundance of Homologous Proteins by Conserved-Plus-Surrogate Peptide Approach: Quantification of UDP Glucuronosyltransferases in Human Tissues

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