Regulation of Drug-Metabolizing Enzymes and Drug Metabolism by Inflammatory Responses

Morgan, Edward T.

doi:10.1016/b978-0-12-802949-7.00002-x

Cited by 19 publications

(38 citation statements)

References 206 publications

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“…The possible clinical effects of bacterial infection (eg, sepsis, Helicobacter pylori), parasitic infections (such as malaria or schistosomiasis), or vaccination on drug clearance will not be examined, as these were reviewed extensively by Morgan in 2017. 8…”

Section: Review Of Clinical Changes In Cyp-mediated Drug Clearance Frmentioning

confidence: 99%

“…[5][6][7] To date, inflammatory disease state effects on CYPs through cytokine modulation have been of greater clinical magnitude and have been more clearly elucidated than inflammatory effects on either transporters or UDP-glucuronyltransferases. 7,8 Effective disease treatment can lead to normalization of these CYP protein concentrations and cause disease-drug interactions, particularly during coadministration of sensitive CYP substrates with a narrow therapeutic index (NTI) such as cyclosporine (a CYP3A substrate), theophylline (CYP1A2), or warfarin (CYP2C9). It is of great importance to consider the severity of the inflammatory disease state and the magnitude of cytokine modulation when considering the potential for disease-drug interaction.…”

mentioning

confidence: 99%

“…In turn, increases in cytokine concentrations can downregulate both hepatic and intestinal metabolizing CYPs, as well as drug transporters and conjugative enzymes such as the uridine diphospho‐glucuronosyltransferases . To date, inflammatory disease state effects on CYPs through cytokine modulation have been of greater clinical magnitude and have been more clearly elucidated than inflammatory effects on either transporters or UDP‐glucuronyltransferases . Effective disease treatment can lead to normalization of these CYP protein concentrations and cause disease–drug interactions, particularly during coadministration of sensitive CYP substrates with a narrow therapeutic index (NTI) such as cyclosporine (a CYP3A substrate), theophylline (CYP1A2), or warfarin (CYP2C9).…”

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confidence: 99%

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Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

Coutant

Hall

2018

The Journal of Clinical Pharma

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The human inflammatory response can result in the alteration of drug clearance through effects on drug-metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)-mediated drug clearance and alter plasma protein binding. Also examined is how albumin, α-1-acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation.

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Section: Review Of Clinical Changes In Cyp-mediated Drug Clearance Frmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

Coutant

Hall

2018

The Journal of Clinical Pharma

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“…However, the metabolism function of liver can be affected by many factors, and the inhibition and induction of drug-metabolizing enzymes are important causes of drug-drug interactions [21][22][23]. Inflammation and oxidative stress have been shown to be one of the potential factors for the inhibition of CYP450 [24]. Therefore, it is important to study whether nanocopper in feed causes liver damage in animals, especially the impacts on drug metabolism enzymes.…”

Section: Introductionmentioning

confidence: 99%

Liver toxicity assessments in rats following sub-chronic oral exposure to copper nanoparticles

Tang

Luo

et al. 2019

Environ Sci Eur

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Background: The widespread use of nano-copper as a feed additive in the absence of toxicological studies has potential risks to humans and animals. Toxicity studies on nano-copper in animals usually exposure from the respiratory tract, however, it is necessary to study the oral exposure toxicity of nano-copper to understand its risks as a feed additive. Results: Currently the hepatotoxicity and mechanism of nano-copper after sub-choronic oral exposure at equivalent doses of 50, 100, and 200 mg/kg/day were evaluated in rats; micro-copper and Cu ions were used as controls. Nanocopper (200 mg/kg) increased serum alanine aminotransferase and aspartate aminotransferase significantly, further promoting hepatic oxidative stress, inflammation, and corresponding histopathological changes, and exhibited significant dose-dependent changes. Nano-copper also decreased the level of nuclear receptors, resulting in significant reductions in mRNA, protein, and activity of hepatic CYP450 enzymes. The molecular mechanisms responsible for these toxic effects involved the signaling pathway of NF-κB, MAPK, and STAT5. Conclusions: Nano-copper caused strong hepatic toxicity by inducing oxidative stress and inflammation. The decreased drug metabolism enzymes lead to nano-copper-drug interaction that provoked the concerns on animalderived food safety.

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“…Therefore, a novel differentiation therapy is sorely needed. The CCAAT enhancer-binding protein α (C/EBPα) is an essential transcription factor for the differentiation of cells in the liver, lung, adipose tissues, and bone marrow [ 4 , 5 , 6 , 7 ]. In the hematopoietic system, C/EBPα is expressed in myeloid cells and is required for granulocytic and monocytic differentiation [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

et al. 2018

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The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure–activity relationship (SAR) of these small molecules in inducing C/EBPα expression—thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.

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Regulation of Drug-Metabolizing Enzymes and Drug Metabolism by Inflammatory Responses

Cited by 19 publications

References 206 publications

Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

Liver toxicity assessments in rats following sub-chronic oral exposure to copper nanoparticles

Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

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