Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

Liu, Zhihua; Li, Lei; Wu, Hong; Hu, Jing; Ma, Jun; Zhang, Qing Yu; Ding, Xinxin

doi:10.1124/dmd.114.061812

Cited by 16 publications

(7 citation statements)

References 39 publications

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“…The CYP2A antibody-inhibition data ( Figure 1B ) further supports these conclusions, and allays any suspicion that the activity difference between the two humanized mouse models was due to contribution by CYP2B6. CYP2B6 has weak activity toward NA ( Cho et al 2006 ); however, although the CYP2A13/2F1-humanized mouse harbors a functional CYP2B6 gene, CYP2B6 protein was not detected in the lung or OM of the TG mouse, with a detection limit of

microsomal protein ( Liu et al 2015 ). It should also be noted that the apparent kinetic parameters determined for lung microsomes may underestimate activities in specific cell types, such as Club cells, which are known to contain higher levels of many P450 enzymes than parenchymal tissue ( Baldwin et al 2004 ; Lakritz et al 1996 ) and may thus possess much greater catalytic efficiency (

) toward NA bioactivation.…”

Section: Discussionmentioning

confidence: 99%

Human CYP2A13 and CYP2F1 Mediate Naphthalene Toxicity in the Lung and Nasal Mucosa of CYP2A13/2F1-Humanized Mice

Carratt

Hartog

et al. 2017

Environ Health Perspect

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Background:The potential carcinogenicity of naphthalene (NA), a ubiquitous environmental pollutant, in human respiratory tract is a subject of intense debate. Chief among the uncertainties in risk assessment for NA is whether human lung CYP2A13 and CYP2F1 can mediate NA’s respiratory tract toxicity.Objectives:We aimed to assess the in vivo function of CYP2A13 and CYP2F1 in NA bioactivation and NA-induced respiratory tract toxicity in mouse models.Methods:Rates of microsomal NA bioactivation and the effects of an anti-CYP2A antibody were determined for lung and nasal olfactory mucosa (OM) from Cyp2abfgs-null, CYP2A13-humanized, and CYP2A13/2F1-humanized mice. The extent of NA respiratory toxicity was compared among wild-type, Cyp2abfgs-null, and CYP2A13/2F1-humanized mice following inhalation exposure at an occupationally relevant dose (10 ppm for 4 hr).Results:In vitro studies indicated that the NA bioactivation activities in OM and lung of the CYP2A13/2F1-humanized mice were primarily contributed by, respectively, CYP2A13 and CYP2F1. CYP2A13/2F1-humanized mice showed greater sensitivity to NA than Cyp2abfgs-null mice, with greater depletion of nonprotein sulfhydryl and occurrence of cytotoxicity (observable by routine histology) in the OM, at 2 or 20 hr after termination of NA exposure, in humanized mice. Focal, rather than gross, lung toxicity was observed in Cyp2abfgs-null and CYP2A13/2F1-humanized mice; however, the extent of NA-induced lung injury (shown as volume fraction of damaged cells) was significantly greater in the terminal bronchioles of CYP2A13/2F1-humanized mice than in Cyp2abfgs-null mice.Conclusion:CYP2F1 is an active enzyme. Both CYP2A13 and CYP2F1 are active toward NA in the CYP2A13/2F1-humanized mice, where they play significant roles in NA-induced respiratory tract toxicity. https://doi.org/10.1289/EHP844

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) toward NA bioactivation.…”

Section: Discussionmentioning

confidence: 99%

Human CYP2A13 and CYP2F1 Mediate Naphthalene Toxicity in the Lung and Nasal Mucosa of CYP2A13/2F1-Humanized Mice

Carratt

Hartog

et al. 2017

Environ Health Perspect

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“…Given the known differences in human vs. rodent metabolism of PCBs [87,[253][254][255][256][257], it will be important to address species differences in translating data from rodent models to human risk. One potential approach for overcoming this challenge would be to use "humanized" mice [258][259][260][261][262][263] that not only express relevant human cytochrome p450 isoforms [87,[264][265][266] but also lack expression of rodent cytochrome P450 enzymes involved in PCB metabolism. Another critical gap is whether the in vitro effects of PCB 11 on neuronal morphogenesis [49,125] translate to the intact developing brain and whether they can be generalized to other contemporary lower-chlorinated PCBs found at relatively high abundance in the serum of pregnant women, such as PCB 28 [37].…”

Section: Conclusion and The Path Forwardmentioning

confidence: 99%

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

Panesar

Kennedy

Stietz

et al. 2020

Toxics

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Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors. ASD affects one in 54 children in the United States, one in 89 children in Europe, and one in 277 children in Asia, with an estimated worldwide prevalence of 1–2%. While there is increasing consensus that ASD results from complex gene x environment interactions, the identity of specific environmental risk factors and the mechanisms by which environmental and genetic factors interact to determine individual risk remain critical gaps in our understanding of ASD etiology. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been linked to altered neurodevelopment in humans. Preclinical studies demonstrate that PCBs modulate signaling pathways implicated in ASD and phenocopy the effects of ASD risk genes on critical morphometric determinants of neuronal connectivity, such as dendritic arborization. Here, we review human and experimental evidence identifying PCBs as potential risk factors for ASD and discuss the potential for PCBs to influence not only core symptoms of ASD, but also comorbidities commonly associated with ASD, via effects on the central and peripheral nervous systems, and/or peripheral target tissues, using bladder dysfunction as an example. We also discuss critical data gaps in the literature implicating PCBs as ASD risk factors. Unlike genetic factors, which are currently irreversible, environmental factors are modifiable risks. Therefore, data confirming PCBs as risk factors for ASD may suggest rational approaches for the primary prevention of ASD in genetically susceptible individuals.

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“…To circumvent the species differences in drug disposition and to create models that more closely reflect human drug response, a number of humanized mouse lines have been reported. In some cases these have also involved humanization for both CAR and PXR (Gong et al, 2005; Dragin et al, 2007; Gonzalez, 2007; Ross et al, 2010; Scheer et al, 2010, 2012a,b, 2015; Scheer and Wolf, 2014; Durmus et al, 2015; Liu et al, 2015). These models have usually also involved the deletion of genes in the orthologous murine gene family.…”

Section: Introductionmentioning

confidence: 99%

An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials

et al. 2019

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Species differences in drug metabolism and disposition can confound the extrapolation of in vivo PK data to man and also profoundly compromise drug efficacy studies owing to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active), and in differential activation of the transcription factors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), which regulate the expression of such enzymes as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug-efficacy testing and also patient-derived xenografts to predict individual patient responses to anticancer drugs. A number of humanized mouse models for cytochrome P450s, CAR, and PXR have been reported. However, the utility of these models has been compromised by the redundancy in P450 reactions across gene families, whereby the remaining murine P450s can metabolize the compounds being tested. To remove this confounding factor and create a mouse model that more closely reflects human pathways of drug disposition, we substituted 33 murine P450s from the major gene families involved in drug disposition, together with Car and Pxr, for human CAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A7. We also created a mouse line in which 34 P450s were deleted from the mouse genome. Using model compounds and anticancer drugs, we demonstrated how these mouse lines can be applied to predict drug-drug interactions in patients and discuss here their potential application in the more informed design of clinical trials and the personalized treatment of cancer.

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Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

Cited by 16 publications

References 39 publications

Human CYP2A13 and CYP2F1 Mediate Naphthalene Toxicity in the Lung and Nasal Mucosa of CYP2A13/2F1-Humanized Mice

Human CYP2A13 and CYP2F1 Mediate Naphthalene Toxicity in the Lung and Nasal Mucosa of CYP2A13/2F1-Humanized Mice

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials

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