Mice With Human Livers

Grompe, Markus; Strom, Stephen C.

doi:10.1053/j.gastro.2013.09.009

Cited by 117 publications

(102 citation statements)

References 56 publications

(60 reference statements)

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“…Many studies supported the presence of human enzyme and transporter expression in humanized mouse livers (Katoh et al, 2005a(Katoh et al, , 2005cNishimura et al, 2005), and pharmacokinetic studies in humanized mice showed the presence of in vivo human metabolites (Okumura et al, 2007;Grompe and Strom, 2013;Bateman et al, 2014). However, other studies using chimeric models showed that the levels of in vivo human metabolites were unpredictable and different from those in humans (De Serres et al, 2011;Liu et al, 2011;Sanoh et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah2/2), recombination activating gene 2 (Rag22/2), and interleukin 2 receptor subunit gamma (IL-2rg 2/2) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids) but lower transforming growth factor beta receptor 2 (TGFBR2) mRNA expression levels (10%) in human hepatocytes and other proliferative markers in mouse nonparenchymal cells (Tgf-b1) and cholangiocytes [plasma membrane-bound, G protein-coupled receptor for bile acids (Tgr5)], suggestive of irregular regeneration processes in hFRGN livers. Changes in gene expression in murine intestine, kidney, and brain of hFRGN mice, in particular, induction of intestinal farnesoid X receptor (Fxr) genes: fibroblast growth factor 15 (Fgf15), mouse ileal bile acid binding protein (Ibabp), small heterodimer partner (Shp), and the organic solute transporter alpha (Osta), were observed. Proteomics revealed persistence of remnant murine proteins (cyotchrome P450 7a-hydroxylase (Cyp7a1) and other enzymes and transporters) in hFRGN livers and suggest the likelihood of mouse activity. When compared with normal human liver tissue, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tb-and ta-muricholic acid-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver fibroblast growth factor receptor 4 (FGFR4), as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, making questionable the use of the preparation for drug metabolism studies.

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Section: Discussionmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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“…Chimeric mice with humanized livers hold considerable advantages for more accurate prediction of human metabolism over conventional in vivo animal or in vitro human systems (Yoshizato et al, 2012;Grompe and Strom, 2013;Peltz, 2013). The ability to predict circulating human metabolites is one of the characteristic features of this model which could satisfy regulatory requirements for the safety testing of drug metabolites (Kamimura et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Formation of the Accumulative Human Metabolite and Human-Specific Glutathione Conjugate of Diclofenac in TK-NOG Chimeric Mice with Humanized Livers

et al. 2014

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39-Hydroxy-49-methoxydiclofenac (VI) is a human-specific metabolite known to accumulate in the plasma of patients after repeated administration of diclofenac sodium. Diclofenac also produces glutathioneconjugated metabolites, some of which are human-specific. In the present study, we investigated whether these metabolites could be generated in humanized chimeric mice produced from TK-NOG mice. After a single oral administration of diclofenac to humanized mice, the unchanged drug in plasma peaked at 0.25 hour and then declined with a half-life (t 1/2 ) of 2.4 hours. 49-Hydroxydiclofenac (II) and 39-hydroxydiclofenac also peaked at 0.25 hour and were undetectable within 24 hours. However, VI peaked at 8 hours and declined with a t 1/2 of 13 hours. When diclofenac was given once per day, peak and trough levels of VI reached plateau within 3 days. Studies with administration of II suggested VI was generated via II as an intermediate. Among six reported glutathione-conjugated metabolites of diclofenac, M1 (5-hydroxy-4-(glutathion-S-yl)diclofenac) to M6 (29-(glutathion-S-yl)monoclofenac), we found three dichlorinated conjugates [M1, M2 (49-hydroxy-39-(glutathion-S-yl)diclofenac), and M3 (5-hydroxy-6-(glutathion-S-yl)diclofenac)], and a single monochlorinated conjugate [M4 (29-hydroxy-39-(glutathion-S-yl)monoclofenac) or M5 (49-hydroxy-29-(glutathion-S-yl)monoclofenac)], in the bile of humanized chimeric mice. M4 and M5 are positional isomers and have been previously reported as human-specific in vitro metabolites likely generated via arene oxide and quinone imine-type intermediates, respectively. The biliary monochlorinated metabolite exhibited the same mass spectrum as those of M4 and M5, and we discuss whether this conjugate corresponded to M4 or M5. Overall, humanized TK-NOG chimeric mice were considered to be a functional tool for the study of drug metabolism of diclofenac in humans.

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“…For example, liver-humanized mice show similarities to the human liver in drug metabolism and toxicity, which are not reflected in normal mice owing to differences in metabolic enzymes and transporters. 100,101 However, genetically engineered mouse models that express the desired human antigen in the same cell types as humans have only been created for lymphoma models so far. 102 Mice with humanized-receptor expression in normal tissues would have the potential to better reflect the distribution and toxicity of mAb variants and could also be used to study pharmacodynamics of radiolabelled constructs.…”

Section: Translation Of Combination Of Internal and External Radiothementioning

confidence: 99%

Improving external beam radiotherapy by combination with internal irradiation

Dietrich¹,

Koi²,

Zöphel³

et al. 2015

BJR

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The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.

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Mice With Human Livers

Cited by 117 publications

References 56 publications

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Formation of the Accumulative Human Metabolite and Human-Specific Glutathione Conjugate of Diclofenac in TK-NOG Chimeric Mice with Humanized Livers

Improving external beam radiotherapy by combination with internal irradiation

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