Drug Metabolism in the Liver

Almazroo, Omar Abdulhameed; Miah, Mohammad K.; Venkataramanan, Raman

doi:10.1016/j.cld.2016.08.001

Cited by 494 publications

(323 citation statements)

References 74 publications

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“…Cytochrome P450 (CYP450) enzymes are the key enzymes in the liver involved in the metabolism of drugs, steroids, vitamins, and other chemicals [30]. CYP450 superfamily is typical to represent most common phase I drug-metabolizing enzymes [31]. For example, CYP1-CYP3 members in the CYP450 families are responsible for the phase I-dependent metabolism of 70-80% clinically used drugs [32].…”

Section: Resultsmentioning

confidence: 99%

Endogenous circadian time genes expressions in the liver of mice under constant darkness

Zhang

et al. 2020

BMC Genomics

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Background: The circadian rhythms regulate physiological functions and metabolism. Circadian Time (CT) is a unit to quantify the rhythm of endogenous circadian clock, independent of light influence. To understand the gene expression changes throughout CT, C57BL/6 J mice were maintained under constant darkness (DD) for 6 weeks, and the liver samples were collected starting at 9:00 AM (CT1), and every 4 h in a 24-h cycle (CT5, CT9, CT13, CT17 and CT21). Total RNA was extracted and subjected to RNA-Seq data (deposited as GSE 133342, L-DD). To compare gene oscillation pattern under normal light-dark condition (LD, GSE114400) and short time (2 days) dark-dark condition (S-DD, GSE70497), these data were retried from GEO database, and the trimmed mean of M-values normalization was used to normalize the three RNA-seq data followed by MetaCycle analysis. Results: Approximate 12.1% of the genes under L-DD exhibited significant rhythmically expression. The top 5 biological processes enriched in L-DD oscillation genes were mRNA processing, aromatic compound catabolic process, mitochondrion organization, heterocycle catabolic process and cellular nitrogen compound mitotic catabolic process. The endogenous circadian rhythms of clock genes, P450 genes and lipid metabolism genes under L-DD were further compared with LD and S-DD. The oscillation patterns were similar but the period and amplitude of those oscillation genes were slightly altered. RT-qPCR confirmed the selected RNA sequence findings. Conclusions: This is the first study to profile oscillation gene expressions under L-DD. Our data indicate that clock genes, P450 genes and lipid metabolism genes expressed rhythmically under L-DD. Light was not the necessary factor for persisting circadian rhythm but influenced the period and amplitude of oscillation genes.

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Section: Resultsmentioning

confidence: 99%

Endogenous circadian time genes expressions in the liver of mice under constant darkness

Zhang

et al. 2020

BMC Genomics

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“…The intestinal epithelial cells have drug pumps and detoxifying enzymes to protect themselves from these environmental threats and can quickly regenerate new cells from the intestinal stem cell compartment. If ingested toxins are absorbed, they make their way to the liver via the portal circulation where they can be metabolized, conjugated, and/or excreted back into the gut (Nakanishi and Tamai, 2015;Almazroo et al, 2017). The intestinal stroma is increasingly recognized as an important part of the stem cell niche, producing Wnts and additional growth factors, and is subject to the same threats as the epithelium.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

et al. 2018

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The gut absorbs dietary nutrients and provides a barrier to xenobiotics and microbiome metabolites. To cope with toxin exposures, the intestinal epithelium is one of the most rapidly proliferating tissues in the body. The stem cell niche supplies essential signaling factors including Wnt proteins secreted by subepithelial myofibroblasts. Unexpectedly, therapeutically effective doses of orally administered PORCN inhibitors that block all Wnt secretion do not affect intestinal homeostasis. We find that intestinal myofibroblasts are intrinsically resistant to multiple xenobiotics, including PORCN inhibitors and the anthracycline antibiotic doxorubicin. These myofibroblasts have high expression of a subset of drug transporters; knockout of Mrp1/Abcc1 enhances drug sensitivity. Tamoxifen administration to Rosa26 mice visually highlights the drug-resistant intestinal stromal compartment and identifies small populations of drug-resistant cells in lung, kidney, and pancreatic islets. Xenobiotic resistance of the Wnt-producing myofibroblasts can protect the intestinal stem cell niche in the face of an unpredictable environment.

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“…The most well‐known drug‐metabolizing enzymes are cytochromes P450 (CYP450s), which consist of oxidases, reductases, and hydrolases . CYP450s are the primary enzymes involved in drug metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…The most well-known drug-metabolizing enzymes are cytochromes P450 (CYP450s), which consist of oxidases, reductases, and hydrolases. [1][2][3] CYP450s are the primary enzymes involved in drug metabolism. They are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use, and they are a major source of variability in drug pharmacokinetics and response.…”

Section: Introductionmentioning

confidence: 99%

Identification of significant protein markers by mass spectrometry after co‐treatment of cells with different drugs: An in vitro survey platform

Huang

Hsieh

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Understanding drug–drug interactions and predicting the side effects induced by polypharmacy are difficult because there are few suitable platforms that can predict drug–drug interactions and possible side effects. Hence, developing a platform to identify significant protein markers of drug–drug interactions and their associated side effects is necessary to avoid adverse effects. Methods Human liver cells were treated with ethosuximide in combination with cimetidine, ketotifen, metformin, metronidazole, or phenytoin. After sample preparation and extraction, mitochondrial proteins from liver cells were isolated and digested with trypsin. Then, peptide solutions were detected using a nano ultra‐performance liquid chromatographic system combined with tandem mass spectrometry. The Ingenuity Pathway Analysis tool was used to simulate drug–drug interactions and identify protein markers associated with drug‐induced adverse effects. Results Several protein markers were identified by the proposed method after liver cells were co‐treated with ethosuximide and other drugs. Several of these protein markers have previously been reported in the literature, indicating that the proposed platform is workable. Conclusions Using the proposed in vitro platform, significant protein markers of drug–drug interactions could be identified by mass spectrometry. This workflow can then help predict indicators of drug–drug interactions and associated adverse effects for increased safety in clinical prescriptions.

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Drug Metabolism in the Liver

Cited by 494 publications

References 74 publications

Endogenous circadian time genes expressions in the liver of mice under constant darkness

Endogenous circadian time genes expressions in the liver of mice under constant darkness

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

Identification of significant protein markers by mass spectrometry after co‐treatment of cells with different drugs: An in vitro survey platform

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