Transcriptional profiling of cytochrome P450 genes in the liver of adult zebrafish, &lt;i&gt;Danio rerio&lt;/i&gt;

Kubota, Akira; Kawai, Yusuke; Yamashita, Natsumi; Lee, Jae Seung; Kondoh, Daisuke; Zhang, Shuangyi; Nishi, Yasunobu; Suzuki, Kazuyuki; Kitazawa, Takio

doi:10.2131/jts.44.347

Cited by 18 publications

(11 citation statements)

References 61 publications

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“…It should be noticed that in this study we used only male rats. However, several studies reported a significant effect of gender on CYP expression in different animal models, i.e., rodents [57], and, more recently, zebrafish [58]. Further studies are needed to ascertain whether a Western diet effect on drug-metabolizing enzymes is related to gender and to analyze the translational impact of this finding.…”

Section: Discussionmentioning

confidence: 99%

Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis

et al. 2019

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Since nutrition might have a significant impact on liver function, we analyzed the early effect of Western-type diet on hepatic tissue and lipid and drug metabolism in Wistar–Kyoto rats (n = 8); eight rats fed with a standard diet were used as controls. Histological analysis of liver tissue was performed, and plasma biochemical parameters were measured. Plasma concentration of six bile acids was determined by ultra-liquid chromatography-tandem mass spectrometry UHPLC-MS/MS. Hepatic gene expressions of enzymes involved in drug and lipid metabolism were assessed by means of real-time reverse transcription (qRT)-PCR. Liver of rats fed with a Western diet did not show macroscopic histological alterations, but number and diameter of lipid droplets increased, as well as DGAT1, GPAT4, SCD, FASN and SREBP2 expression. Furthermore, Western diet-fed animals showed an increase in the activation of hepatic stellate cells and macrophage number in liver tissue, as well as a significant increase in AST and bilirubin levels (p < 0.01), and in the LDL:HDL cholesterol ratio (p < 0.001). Plasma chenodeoxycholic acid concentration increased significantly, whereas cholic acid decreased (p < 0.05), and cytochrome P450 genes were generally downregulated. Significant changes in hepatic lipid and drug metabolism are early induced by the Western diet, prior to steatosis development. Such changes are associated with a peculiar alteration in circulating bile acids, which could represent an early marker of non-alcoholic fatty liver disease (NAFLD) development.

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Section: Discussionmentioning

confidence: 99%

Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis

et al. 2019

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“…It was, therefore, suggested to play a central role in liver physiology and/or xenobiotic biotransformation (Kubota et al 2019). However, in male zebrafish CYP3A65 mRNA accounts for only 6.5% of the total hepatic CYP mRNA content (Kubota et al 2019). This sex-dimorphic expression is contrary to that found in adult killifish (Fundulus heteroclitus), where male fish displayed up to 2.5 -fold higher hepatic CYP3A65 mRNA and protein than female killifish (Hegelund and Celander 2003).…”

Section: Spatiotemporal Expression Patterns Of the Cyp3 Familymentioning

confidence: 99%

“…However, expression of CYP1A does not only vary with age, but also with sex. While CYP1A mRNA accounts for 14.5% of the total hepatic CYP mRNA contents in male zebrafish, it accounts for only 5% in female zebrafish (Kubota et al 2019 ).…”

Section: Spatial and Temporal Cyp Gene Expression Patternsmentioning

confidence: 99%

“…CYP2J1 , which has been suggested to play a role in gonadal development and ovarian follicular development (Wang et al 2007 ) and CYP2K6 (Wang-Buhler et al 2005 ) were both found to be constitutively expressed in gonads of adult zebrafish, however, at higher levels in female than in male zebrafish. Moreover, by transcriptional analysis of liver samples, Kubota et al, ( 2019 ) and Zheng et al ( 2013 ) identified several CYP2 genes having sex-biased expression levels. These include CYP2N13 , CYP2K6 , CYP2AD2 and CYP2AA4 .…”

Section: Spatial and Temporal Cyp Gene Expression Patternsmentioning

confidence: 99%

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Cytochrome P450-dependent biotransformation capacities in embryonic, juvenile and adult stages of zebrafish (Danio rerio)—a state-of-the-art review

Loerracher

Braunbeck

2021

Arch Toxicol

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Given the strong trend to implement zebrafish (Danio rerio) embryos as translational model not only in ecotoxicological, but also toxicological testing strategies, there is an increasing need for a better understanding of their capacity for xenobiotic biotransformation. With respect to the extrapolation of toxicological data from zebrafish embryos to other life stages or even other organisms, qualitative and quantitative differences in biotransformation pathways, above all in cytochrome P450-dependent (CYP) phase I biotransformation, may lead to over- or underestimation of the hazard and risk certain xenobiotic compounds may pose to later developmental stages or other species. This review provides a comprehensive state-of-the-art overview of the scientific knowledge on the development of the CYP1-4 families and corresponding phase I biotransformation and bioactivation capacities in zebrafish. A total of 68 publications dealing with spatiotemporal CYP mRNA expression patterns, activities towards mammalian CYP-probe substrates, bioactivation and detoxification activities, as well as metabolite profiling were analyzed and included in this review. The main results allow for the following conclusions: (1) Extensive work has been done to document mRNA expression of CYP isoforms from earliest embryonic stages of zebrafish, but juvenile and adult zebrafish have been largely neglected so far. (2) There is insufficient understanding of how sex- and developmental stage-related differences in expression levels of certain CYP isoforms may impact biotransformation and bioactivation capacities in the respective sexes and in different developmental stages of zebrafish. (3) Albeit qualitatively often identical, many studies revealed quantitative differences in metabolic activities of zebrafish embryos and later developmental stages. However, the actual relevance of age-related differences on the outcome of toxicological studies still needs to be clarified. (4) With respect to current remaining gaps, there is still an urgent need for further studies systematically assessing metabolic profiles and capacities of CYP isoforms in zebrafish. Given the increasing importance of Adverse Outcome Pathway (AOP) concepts, an improved understanding of CYP capacities appears essential for the interpretation and outcome of (eco)toxicological studies.

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“…These metabolic regulators are pre‐eminent in the selection of an animal model for drug toxicity screening procedures (Browning & Horton, 2004). The transcriptional profile of CYP genes shows gender‐specific expression levels, but the major CYP genes present in both the sexes that regulate the xenobiotic metabolism at primary verge are cyp2ad2, cyp3a65, cyp1a, cyp2p9 and cyp2y3 (Alderton et al, 2010; Goldstone et al, 2010; Kubota et al, 2019).…”

Section: Hepatic System Of Zebrafishmentioning

confidence: 99%

Zebrafish: An emerging model system to study liver diseases and related drug discovery

Katoch

Patial

2020

J of Applied Toxicology

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The zebrafish has emerged as a powerful vertebrate model for studying liverassociated disorders. Liver damage is a crucial problem in the process of drug development and zebrafish have proven to be an important tool for the highthroughput screening of drugs for hepatotoxicity. Although the structure of the zebrafish liver differs to that of mammals, the fundamental physiologic processes, genetic mutations and manifestations of pathogenic responses to environmental insults exhibit much similarity. The larval transparency of the zebrafish is a great advantage for real-time imaging in hepatic studies. The zebrafish has a broad spectrum of cytochrome P450 enzymes, which enable the biotransformation of drugs via similar pathways as mammals, including oxidation, reduction and hydrolysis reactions. In the present review, we appraise the various drugs, chemicals and toxins used to study liver toxicity in zebrafish and their similarities to the rodent models for liverrelated studies. Interestingly, the zebrafish has also been effectively used to study the pathophysiology of nonalcoholic and alcoholic fatty liver disease. The genetic models of liver disorders and their easy manipulation provide great opportunity in the area of drug development. The zebrafish has proven to be an influential model for the hepatic system due to its invertebrate-like advantages coupled with its vertebrate biology. The present review highlights the pivotal role of zebrafish in bridging the gap between cell-based and mammalian models.

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Transcriptional profiling of cytochrome P450 genes in the liver of adult zebrafish, <i>Danio rerio</i>

Cited by 18 publications

References 61 publications

Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis

Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis

Cytochrome P450-dependent biotransformation capacities in embryonic, juvenile and adult stages of zebrafish (Danio rerio)—a state-of-the-art review

Zebrafish: An emerging model system to study liver diseases and related drug discovery

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