The metabolism of 7‐ethoxycoumarin in human liver microsomes and the effect of primary biliary cirrhosis: implications for studies of drug metabolism in liver disease.

Woodhouse, K. W.; Mitchison, HC; Mutch, Elaine; Wright, Peter V.; Rawlins,; James, O.F.W.

doi:10.1111/j.1365-2125.1985.tb02801.x

Cited by 8 publications

(5 citation statements)

References 8 publications

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“…Several previous studies reported that the activities of several CYPs, including CYP1A2, CYP2A6, CYP2D6, CYP2C19, CYP2E1, and CYP3A were decreased in cirrhosis patients relative to healthy subjects [15, 16, 19-21, 31-35]. However, in the current study we found that the CYP2D6 CL int value from the cirrhosis patient subgroup was significantly higher than that for HCC patients without cirrhosis.…”

Section: Discussioncontrasting

confidence: 88%

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma

Zhou

Wen

Li³

et al. 2016

Oncotarget

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The lack of information concerning individual variation in drug-metabolizing enzymes is one of the most important obstacles for designing personalized medicine approaches for hepatocellular carcinoma (HCC) patients. To assess cytochrome P450 (CYP) in the metabolism of endogenous and exogenous molecules in an HCC setting, the activity changes of 10 major CYPs in microsomes from 105 normal and 102 HCC liver tissue samples were investigated. We found that CYP activity values expressed as intrinsic clearance (CLint) differed between HCC patients and control subjects. HCC patient samples showed increased CLint for CYP2C9, CYP2D6, and CYP2E1 compared to controls. Meanwhile, CYP1A2, CYP2C8, and CYP2C19 CLint values decreased and CYP2A6, CYP2B6, and CYP3A4/5 activity was unchanged relative to controls. For patients with HCC accompanied by fibrosis or cirrhosis, the same activity changes were seen for the CYP isoforms, except for CYP2D6 which had higher values in HCC patients with cirrhosis. Moreover, CYP2D6*10 (100C>T), CYP2C9*3 (42614 A>C), and CYP3A5*3 (6986A>G) polymorphisms had definite effects on enzyme activities. In the HCC group, the CLint of CYP2D6*10 mutant homozygote was decreased by 95% compared to wild-type samples, and the frequency of this homozygote was 2.8-fold lower than the controls.In conclusion, the activities of CYP isoforms were differentially affected in HCC patients. Genetic polymorphisms of some CYP enzymes, especially CYP2D6*10, could affect enzyme activity. CYP2D6*10 allelic frequency was significantly different between HCC patients and control subjects. These findings may be useful for personalizing the clinical treatment of HCC patients as well as predicting the risk of hepatocarcinogenesis.

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Section: Discussioncontrasting

confidence: 88%

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma

Zhou

Wen

Li³

et al. 2016

Oncotarget

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“…incorporate change in the in vivo hepatic enzyme activity by administering selective probe substrates to patients with liver disease or by measuring their enzyme activity or protein abundance (by Western blotting) in vitro (Johnson et al, 2010); however, such studies are not comprehensive as they are limited to enzymes that have selective probes or antibodies (Woodhouse et al, 1985;Johnson et al, 2010). Therefore, the aims of this study were 1) to determine the effect of HCV and alcoholic cirrhosis on protein abundance of multiple hepatic phase 1 and phase 2 drug-metabolizing enzymes (DMEs) using quantitative targeted proteomics and 2) to determine whether the protein abundance data in cirrhotic versus noncirrhotic (control) livers can improve prediction of the disposition of drugs in cirrhotic subjects that are metabolized (e.g., zidovudine) or metabolized and transported (e.g., morphine).…”

Section: Introductionmentioning

confidence: 99%

Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study

Prasad¹,

Bhatt²,

Johnson³

et al. 2018

Drug Metabolism and Disposition

119

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To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( = 27) or hepatitis C (HCV, = 30) cirrhotic versus noncirrhotic (control) livers ( = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.

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“…Metabolism of 7-ethoxycoumarin has been studies in human liver slices [ 12 ] and microsomes [ 11 , 13 ]. O-deethylation, and its subsequential glucuronidation and sulfation were reported with three dominant metabolites, 7-hydroxycoumarin, coumarin-7-O-glucuronide, and coumarin-7-O-sulfate.…”

Section: Resultsmentioning

confidence: 99%

“…Metabolism of 7-ethoxycoumarin in human liver microsomes was studied as early as in 1985 [ 7 - 10 ]. Its primary metabolic pathways have been reported as O-deethylation and subsequential glucuronidation and sulfation in in vitro human [ 11 - 13 ], monkey [ 12 , 14 ], dog [ 15 ], rat [ 12 , 16 - 23 ], pig [ 12 , 15 , 24 ], mouse [ 12 , 18 ], rabbit [ 25 ], hen [ 26 ], trout [ 27 ] and bacterial systems [ 28 - 32 ]. Metabolites and Metabolic pathways of 7-ethoxycoumarin in humans, monkeys, dogs and rats reported in the literatures, are summarized in Scheme 1 .…”

Section: Introductionmentioning

confidence: 99%

In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS

Feng

Wen

Stauber

2018

DML

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Most of new metabolites via oxidative ring-opening and glutathionation were identified. Species differences in metabolism of 7-ethoxylcoumarin in hepatocytes were observed. The analysis of metabolites suggests that 7-ethoxylcoumarin may undergo 3,4-epoxidation responsible for formation of glutathione and its derived cysteine conjugates, carboxylic acid and its glucuronides, glucosides and sulfate.

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The metabolism of 7‐ethoxycoumarin in human liver microsomes and the effect of primary biliary cirrhosis: implications for studies of drug metabolism in liver disease.

Cited by 8 publications

References 8 publications

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma

Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study

In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS

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