Generation and Characterization of a Novel <i>Cyp2a(4/5)bgs</i>-Null Mouse Model

Wei, Yuan; Li, Lei; Zhou, Xin; Zhang, Qing Yu; Dunbar, Anwar; Liu, Fang; Kluetzman, Kerri; Yang, Weizhu; Ding, Xinxin

doi:10.1124/dmd.112.048736

Cited by 33 publications

(26 citation statements)

References 59 publications

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“…1A). As reported recently, the anti-CYP2A5 polyclonal antibody detects a nonspecific band in the lungs of both Cyp2a5-null mice and the CYP2A13-humanized mice (Wei et al, 2013). As expected, the CYP2A13 band was not detected in lung microsomes from the Cyp2a5-null mice, which served as a negative control.…”

Section: Resultssupporting

confidence: 83%

Suppression of Pulmonary CYP2A13 Expression by Carcinogen-Induced Lung Tumorigenesis in a CYP2A13-Humanized Mouse Model

Liu

Megaraj

et al. 2015

Drug Metab Dispos

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CYP2A13 is a human cytochrome P450 (P450) enzyme important in the bioactivation of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). CYP2A13 expression levels vary dramatically among lung biopsy samples from patients, presumably owing in part to a suppression of CYP2A13 expression by disease-associated inflammation. Here, we determined whether CYP2A13 expression in the lungs of CYP2A13-humanized mice is suppressed by the presence of lung tumors. Tissues from an NNK lung tumor bioassay were examined. CYP2A13-humanized mice (95-100%) had multiple lung tumors at 16 weeks after NNK (30 or 50 mg/kg) treatment; whereas only ∼9% of saline-treated CYP2A13-humanized mice had lung tumor (∼1/lung). Mice with lung tumors, from the NNK-treated groups, were used for dissecting adjacent tumor-free lung tissues; whereas mice without visible lung tumors, from the saline-treated group, were used as controls. Compared with the controls, the levels of CYP2A13 protein and mRNA were both reduced significantly (by ‡50%) in the NNK-treated groups. The levels of mouse CYP2B10 and CYP2F2 mRNAs were also significantly lower in the dissected normal lung tissues from tumor-bearing mice than in lungs from the control mice. Pulmonary tissue levels of three proinflammatory cytokines, tumor necrosis factor alpha, interferon gamma, and interleukin-6, were significantly higher in the tumorbearing mice than in the controls, indicating occurrence of low-grade lung inflammation at the time of necropsy. Taken together, these findings support the hypothesis that CYP2A13 levels in human lungs can be suppressed by disease-associated inflammation in tissue donors, a scenario causing underestimation of CYP2A13 levels in healthy lungs.

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Section: Resultssupporting

confidence: 83%

Suppression of Pulmonary CYP2A13 Expression by Carcinogen-Induced Lung Tumorigenesis in a CYP2A13-Humanized Mouse Model

Liu

Megaraj

et al. 2015

Drug Metab Dispos

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“…Here, we used a Cyp2a(4/5)bgs-null mouse model (Wei et al, 2013) to study the impact of nicotine metabolism on nicotine's pharmacological and behavioral effects. In this mouse model, a number of P450 genes known or potentially involved in nicotine metabolism are deleted, including two Cyp2a (2a4 and 2a5) and all five Cyp2b (2b9, 2b10, 2b13, 2b19, and 2b23).…”

Section: Introductionmentioning

confidence: 99%

Impact of Nicotine Metabolism on Nicotine’s Pharmacological Effects and Behavioral Responses: Insights from a Cyp2a(4/5)bgs-Null Mouse

Jia

Zhou

et al. 2013

J Pharmacol Exp Ther

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Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgsnull] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed .90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgsnull and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgsnull mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.

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“…Other studies have shown possible roles of b-catenin and the two-pore K + channel Kcnk1 in the sex difference in PB-induced the hepatocyte proliferation (Braeuning et al, 2011;Saito et al, 2013). PB is not a preferred substrate for CYP2B (Pacifici, 2016), although the clearance of another barbiturate, pentobarbital, in mice appeared to involve enzymes encoded by the Cyp2a(4/5)bgs gene cluster (Wei et al, 2013). It is unclear whether the loss of the Cyp2abgs genes would cause a change in PB metabolism, but there has been no report demonstrating a role for PB metabolites in stimulating hepatocyte proliferation.…”

Section: Cyp2b and Pb-induced Hepatocyte Proliferationmentioning

confidence: 96%

“…Among the deleted genes, only Cyp2a4/5 and Cyp2b9/10/13 are expressed in liver, and Cyp2a4 and Cyp2b9/13 are female predominant (Damiri et al, 2012;Li et al, 2013). The deletion of the gene cluster did not lead to any notable developmental or morphologic changes, and there was no significant compensatory change in the expression of CPR or various other major P450 enzymes, including CYP2C, CYP3A, CYP2E1, and CYP1A1/2 (Wei et al, 2013). A report of a Cyp2b-knockdown mouse also showed absence of any notable biologic phenotypes (Damiri et al, 2012).…”

Section: Introductionmentioning

confidence: 91%

“…We recently reported the generation and characterization of a Cyp2a(4/5)bgs-null mouse model, in which Cyp2a4, Cyp2a5, all five Cyp2b genes, Cyp2g1, and Cyp2s1 are deleted Wei et al, 2013). Among the deleted genes, only Cyp2a4/5 and Cyp2b9/10/13 are expressed in liver, and Cyp2a4 and Cyp2b9/13 are female predominant (Damiri et al, 2012;Li et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice

Bao

Zhang

et al. 2017

Drug Metab Dispos

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Phenobarbital (PB) promotes liver tumorigenesis in rodents, in part through activation of the constitutive androstane receptor (CAR) and the consequent changes in hepatic gene expression and increases in hepatocyte proliferation. A typical effect of CAR activation by PB is a marked induction of Cyp2b10 expression in the liver; the latter has been suspected to be vital for PB-induced hepatocellular proliferation. This hypothesis was tested here by using a Cyp2a(4/5)bgs-null (null) mouse model in which all Cyp2b genes are deleted. Adult male and female wild-type (WT) and null mice were treated intraperitoneally with PB at 50 mg/kg once daily for 5 successive days and tested on day 6. The liver-to-body weight ratio, an indicator of liver hypertrophy, was increased by 47% in male WT mice, but by only 22% in male Cyp2a(4/5)bgs-null mice, by the PB treatment. The fractions of bromodeoxyuridine-positive hepatocyte nuclei, assessed as a measure of the rate of hepatocyte proliferation, were also significantly lower in PB-treated male null mice compared with PB-treated male WT mice. However, whereas few proliferating hepatocytes were detected in saline-treated mice, many proliferating hepatocytes were still detected in PB-treated male null mice. In contrast, female WT mice were much less sensitive than male WT mice to PB-induced hepatocyte proliferation, and PB-treated female WT and PB-treated female null mice did not show significant difference in rates of hepatocyte proliferation. These results indicate that CYP2B induction plays a significant, but partial, role in PB-induced hepatocyte proliferation in male mice.

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Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Cited by 33 publications

References 59 publications

Suppression of Pulmonary CYP2A13 Expression by Carcinogen-Induced Lung Tumorigenesis in a CYP2A13-Humanized Mouse Model

Suppression of Pulmonary CYP2A13 Expression by Carcinogen-Induced Lung Tumorigenesis in a CYP2A13-Humanized Mouse Model

Impact of Nicotine Metabolism on Nicotine’s Pharmacological Effects and Behavioral Responses: Insights from a Cyp2a(4/5)bgs-Null Mouse

Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice

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