A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity

Abstract

Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug-drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives.

Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice

“…The generation and application of humanized mouse models to translate animal pharmacokinetics, metabolism, toxicity and target validation to humans have gained significant favor over the past 5–10 years [8–11]. Because of species differences noted previously in the PepT1-mediated uptake kinetics of GlySar in transformed yeast [7], Hu and coworkers [12] approached this challenge by developing and characterizing a mouse line humanized for the intestinal peptide transporter PepT1 .…”

“…Using a yeast system expressing mouse, rat and human PepT1 cDNA, a species difference in PepT1 activity was demonstrated for glycylsarcosine (GlySar) where the uptake was saturable in all three species and 3- to 5-fold differences were observed in their K m values [7]. Recognizing the need to improve prediction of human pharmacokinetics, drug-drug interactions and safety concerns because of species differences, genetically humanized and chimeric liver humanized mouse models were proposed by Scheer and Wilson [8]. At present, most humanized mouse models have focused on addressing the species differences in drug metabolizing enzymes [9], xenobiotic receptors [10, 11] and, to a lesser extent, drug transporters [12].…”

Comparing expression and activity of PCSK9 in SPRET/EiJ and C57BL/6J mouse strains shows lack of correlation with plasma cholesterol

“…A more cogent proof of the implication of PCSK9 deficiency to these phenotypes in the SPRET mouse would be their reversal through replacement therapy involving chronic intravenous administration of a recombinant form of the protein or its transgene-mediated expression in the liver. More applicable to human biology would be the exploration of these phenotypic traits in a chimeric mouse model of transplanted with human liver [38], [39] that carries an inactive PCSK9 gene.…”

Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals

“…Hence, humanized CYP1 knock-in mice [(Derkenne et al , 2005; Dragin et al , 2006; Dragin et al , 2007; Jiang et al , 2005; Shi et al , 2008), reviewed in (Cheung and Gonzalez, 2008)] should also be studied. Subsequently, various other studies using Cyp2 , Cyp3 and Cyp4 single-knockout mice, compared with the (replaced) human orthologous CYP , CYP3 , CYP4 gene knocked-in (Scheer and Wolf, 2014; Scheer and Wilson, 2016), should also be carried out.…”