Highly homologous mouse Cyp2a4 and Cyp2a5 genes are differentially expressed in the liver and both express long non-coding antisense RNAs

Nail, Alexandra N.; Spear, Brett T.; Peterson, Martha L.

doi:10.1016/j.gene.2020.145162

Cited by 4 publications

(6 citation statements)

References 56 publications

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“…CYP2A4 is strongly female-biased in the liver, while CYP2A5 is not . The female mouse expresses both Cyp2a4 and Cyp2a5 , whereas the male mouse is almost exclusively expressed by Cyp2a5 . Male mice were therefore used in the microsomal metabolism and pharmacokinetic experiments.…”

Section: Discussionmentioning

confidence: 99%

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Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition

Zeng

Tan

et al. 2022

Mol. Pharmaceutics

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Systemic exposure of metronidazole is increased in patients with inflammatory bowel diseases (IBDs), while the underlying mechanism remains unknown. Here, we aim to decipher the mechanisms by which experimental colitis regulates metronidazole disposition in mice. We first confirmed that the systemic exposure of metronidazole was elevated in dextran sulfate sodium (DSS)-induced experimental colitis. Hepatic microsomal incubation with metronidazole revealed that the production rate of 2-hydroxymetronidazole was inhibited, suggestive of a diminished hydroxylation reaction upon colitis. Remarkably, the hydroxylation reaction of metronidazole was selectively catalyzed by CYP2A5, which was downregulated in the liver of colitis mice. In addition, hepatic nuclear factor (NF)-κB (a prototypical and critical signaling pathway in inflammation) was activated in colitis mice. Luciferase reporter and chromatin immunoprecipitation assay indicated that NF-κB downregulated Cyp2a5 transcription through binding to an NF-κB binding site (−1711 to −1720 bp) in the promoter. We further verified that the regulatory effects of colitis on CYP2A5 depended on the disease itself rather than the DSS compound. First, one-day administration of DSS did not alter mRNA and protein levels of CYP2A5. Moreover, CYP2A5 was suppressed in the Il-10–/– spontaneously developing colitis model. Furthermore, Cyp2a5 expression was downregulated in both groups of mice with modest or severe colitis, whereas the expression change was much more significant in severe colitis as compared to modest colitis. Altogether, activated hepatic NF-κB in experimental colitis regulates CYP2A5 and metronidazole disposition, revealing the mechanism of pharmacokinetic instability under IBDs, and providing a theoretical foundation for rational drug use in the future.

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Section: Discussionmentioning

confidence: 99%

“…38 The female mouse expresses both Cyp2a4 and Cyp2a5, whereas the male mouse is almost exclusively expressed by Cyp2a5. 39 Male mice were therefore used in the microsomal metabolism and pharmacokinetic experiments. The results revealed a critical role of CYP2A5 in colitis-regulating metronidazole disposition.…”

Section: Discussionmentioning

confidence: 99%

Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition

Zeng

Tan

et al. 2022

Mol. Pharmaceutics

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“…Therefore, we needed to assess the impact of Cyp2a on the results of our Cyp2c expression analysis. There are reports of Cyp2a4 and Cyp2a5 mRNA expression levels analyzed over the course of liver development (Nail et al., 2021; Poca et al., 2017). Cyp2a4 and Cyp2a5 mRNA expression in the mouse liver at P28 is minimal in both males and females, and is reported to increase dramatically only in females by P56.…”

Section: Discussionmentioning

confidence: 99%

“…Nail et al. also reported that long‐stranded antisense sequences of Cyp2a4 and Cyp2a5 mRNA are expressed from 14 days of age (Nail et al., 2021). Thus, it suggested that these antisense sequences normally inhibit the translation of Cyp2a4 and Cyp2a5 mRNA into protein.…”

Section: Discussionmentioning

confidence: 99%

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Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage

Kawamura

Ichikawa

Hatogai

et al. 2022

Biopharm & Drug Disp

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In the adult liver, drug-metabolizing enzymes such as cytochrome P450 (CYP) efficiently metabolize drugs by forming an expression pattern called "zonation" structure around the central veins (CV). However, most previous studies on CYPs have focused on the expression levels of CYP mRNA and proteins in the whole liver.In this study, we analyzed not only the expression levels of Cyp2c family mRNAs and proteins in mice during fetal liver development, but also the relationship with their localization. In the whole fetal liver, Cyp2c mRNA and protein were hardly expressed. On the other hand, zonation analysis results showed that only some cells around the CV of the fetal liver expressed Cyp2c. In addition, the protein expression level of Cyp2c in the whole liver during the neonatal period started from postnatal day (P) 7 in both males and females, while the zonation was weakly formed from P5.This study suggested that fetal liver cannot metabolize Cyp2c substrate drugs transferred from mother to fetus due to the low expression of Cyp2c and unformed zonation. The expression level of Cyp2c protein in neonates was lower than that in adult liver, and the zonation structure was not clear, suggesting that drug metabolism was not sufficient. Furthermore, this study revealed that the expression level of Cyp2c does not correlate with the formation of zonation structures, because Cyp2c expression is found in hepatocytes near the CV even in the fetal and neonatal stages, when Cyp2c protein expression is hardly detectable in the whole liver.

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Oral exposure to polyethylene microplastics induces inflammatory and metabolic changes and promotes fibrosis in mouse liver.

Djouina,

Waxin,

Dubuquoy

et al. 2023

Ecotoxicology and Environmental Safety

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Highly homologous mouse Cyp2a4 and Cyp2a5 genes are differentially expressed in the liver and both express long non-coding antisense RNAs

Cited by 4 publications

References 56 publications

Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition

Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition

Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage

Oral exposure to polyethylene microplastics induces inflammatory and metabolic changes and promotes fibrosis in mouse liver.

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