Investigation of nonalcoholic fatty liver disease-induced drug metabolism by comparative global toxicoproteomics

Na, Ann-Yae; Jo, Jung Jae; Kwon, Oh Kwang; Shrestha, Riya; Cho, Pil Joung; Kim, Kyu Min; Ki, Sung Hwan; Lee, Tae Hee; Jeon, Tae Won; Jeong, Tae Cheon; Lee, Sangkyu

doi:10.1016/j.taap.2018.05.021

Cited by 9 publications

(4 citation statements)

References 39 publications

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“…Previous reports also support our ndings. Li et al reported that the activity and expression of Cyp450 enzymes, including Cyp1a2, Cyp3a11, and Cyp2c29, decrease in the NASH group induced by MCD diet [40,41]. By contrast, the number of host Cyp450s involved in those studies is individual, whereas six host Cyp450s were simultaneously investigated in our study, which is almost responsible for the metabolism of over 80% of clinically used drugs.…”

Section: Discussioncontrasting

confidence: 58%

Gut Microbiota and Host Cyp450s Co-contribute to Pharmacokinetic Variability in Mice With Non-Alcoholic Steatohepatitis: Vary From Drug to Drug

Guo

Chen

et al. 2021

Preprint

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Background: Pharmacokinetic variability in disease state is common in clinical practice, but the underlying mechanism remains unclear. We aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH).Methods: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administration of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol compared with the control group. The pharmacokinetic variability of the drugs and its relation with changes of gut microbiota and host Cyp450s were compared and analyzed.Results: The exposure of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity of the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in host Cyp2c65. However, gut microbiota and host Cyp450s exerted minimal effect on the pharmacokinetic variability of metoprolol.Conclusions: Gut microbiota and host Cyp450s co-contribute the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug.

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Section: Discussioncontrasting

confidence: 58%

Gut Microbiota and Host Cyp450s Co-contribute to Pharmacokinetic Variability in Mice With Non-Alcoholic Steatohepatitis: Vary From Drug to Drug

Guo

Chen

et al. 2021

Preprint

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“…Meanwhile, the levels of cytochrome P450 proteins, such as Cyp2a4, Cyp2c29, and Cyp2c70, were decreased in the liver during malaria in pregnancy. The levels of cytochrome P450 proteins are altered in patients with non-alcoholic fatty liver disease [ 32 ] and a corresponding animal model [ 33 , 34 ]. These findings suggest that inflammation or infection affect levels of cytochrome P450 proteins in the liver.…”

Section: Discussionmentioning

confidence: 99%

The association between acute fatty liver disease and nitric oxide during malaria in pregnancy

Niikura

Fukutomi

Mineo

et al. 2021

Malar J

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Background Liver disease is a common feature of malaria in pregnancy, but its pathogenesis remains unclear. Methods To understand the pathogenesis of liver disease during malaria in pregnancy, comparative proteomic analysis of the liver in a mouse model of malaria in pregnancy was performed. Results Decreased levels of mitochondrial and peroxisomal proteins were observed in the livers of pregnant mice infected with the lethal rodent malaria parasite Plasmodium berghei strain NK65. By contrast, increased levels of perilipin-2, amyloid A-1, and interferon (IFN)-γ signalling pathway-related proteins were observed in the livers of infected pregnant mice, suggesting that IFN-γ signalling may contribute to the development of liver disease during malaria in pregnancy. IFN-γ signalling is a potential trigger of inducible nitric oxide synthase (iNOS) expression. Liver disease associated with microvesicular fatty infiltration and elevated liver enzymes in pregnant wild-type mice infected with malaria parasites was improved by iNOS deficiency. Conclusions In this study, a causative role of iNOS in liver disease associated with microvesicular fatty infiltration during malaria in pregnancy was demonstrated. These findings provide important insight for understanding the role of iNOS-mediated metabolic responses and the pathogenesis of high-risk liver diseases in pregnancy, such as acute fatty liver.

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“…Microsomal protein expression of CYP2C19 also decreased with the successive progression of the liver disease from NAFLD to NASH (11). Na et al demonstrated from in vitro and in vivo Cyp cocktail assays, Cyp1A, Cyp2B, Cyp2C and Cyp3A were significantly decreased, whereas Cyp2D remained unchanged in MCD diet mice as compared to normal mice (25). Jamwal et al (2018) studied the association of NAFLD, NASH and diabetes mellitus on CYP3A4 activity in human liver tissue from brain dead donors (26).…”

Section: Case Studies Highlighting Impact Of Nash On Adme Propertiesmentioning

confidence: 98%

Non-alcoholic Steatohepatitis (NASH) Drug Discovery – Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development

2018

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Number of drugs with different mechanisms of actions is undergoing clinical trials for non-alcoholic steatohepatitis (NASH). Given the complexity of the disease with respect to pathophysiology in the liver and associated changes in the renal function, it becomes apparent that a clear ADME (absorption, distribution, metabolism and excretion) strategy needs to be put in place for a successful nomination of a drug candidate for NASH. This review discusses using in vitro and in vivo ADME screens to understand the properties of drugs and to establish whether or not the chosen drug(s) can overcome the challenges related hepatic and renal transporters covering both uptake and efflux mechanisms imposed by NASH. A complete panel of in vivo preclinical experiments including a 14C-labeled study are proposed in NASH animal models to delineate the problematic areas for early drug development. Furthermore, a framework is provided with respect to the clinical pharmacology studies early in clinical development to characterise in an unbiased manner, the altered pharmacokinetics of drug in NASH patients for optimizing the dose selection for late phase clinical development. Because NASH patients have other co-morbid conditions and are prescribed co-medications for treating blood pressure, type 2 diabetes mellitus, obesity, dyslipidemia and many more disorders, it is also suggested to examine the drug-drug interaction potential by performing a cocktail probe study to cover a broad range of cytochrome P450 (CYP) enzymes and transporters.

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Investigation of nonalcoholic fatty liver disease-induced drug metabolism by comparative global toxicoproteomics

Cited by 9 publications

References 39 publications

Gut Microbiota and Host Cyp450s Co-contribute to Pharmacokinetic Variability in Mice With Non-Alcoholic Steatohepatitis: Vary From Drug to Drug

Gut Microbiota and Host Cyp450s Co-contribute to Pharmacokinetic Variability in Mice With Non-Alcoholic Steatohepatitis: Vary From Drug to Drug

The association between acute fatty liver disease and nitric oxide during malaria in pregnancy

Non-alcoholic Steatohepatitis (NASH) Drug Discovery – Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development

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