CpG methylation of the mouse CYP1A2 promoter

Jin, B R; Park, Duk Woong; Nam, Ki-Whan; Oh, Goo Taeg; Lee, Yong-Soon; Ryu, Doug-Young

doi:10.1016/j.toxlet.2004.03.016

Cited by 25 publications

(15 citation statements)

References 35 publications

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“…Low levels of CYP2E1 mRNA in human fetal, neonatal, and adult kidney and lung tissue were also associated with extensive methylation of the same region of the gene (Vieira et al, 1998). A similar phenomenon has been reported for postnatal activation of Cyp1a2 in mice (Jin et al, 2004).…”

Section: Epigenetic Regulation Of Adme Genes During Developmentsupporting

confidence: 75%

Epigenetic Regulation of ADME-Related Genes: Focus on Drug Metabolism and Transport

Zhong

Leeder

2013

Drug Metab Dispos

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Section: Epigenetic Regulation Of Adme Genes During Developmentsupporting

confidence: 75%

Epigenetic Regulation of ADME-Related Genes: Focus on Drug Metabolism and Transport

Zhong

Leeder

2013

Drug Metab Dispos

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“…Previously, we demonstrated that DNA methylation on the CYP1A1 enhancer prevents AhR binding and inhibits CYP1A1 induction in human prostate cancer (Okino et al, 2006); others have shown that the CYP1A2 promoter is methylated in mouse tissues (Jin et al, 2004). Our analysis of DNA methylation (Fig.…”

Section: Resultsmentioning

confidence: 62%

“…We suspect that the growth of cells as a monolayer culture inactivates this region. Indeed, the expression of CYP1A2 in primary hepatocytes is known to dramatically decrease over time, whereas the extent of CYP1A2 promoter methylation increases (Nemoto and Sakurai, 1993;Jin et al, 2004). Future studies that determine the significance of this putative control region may provide novel insights into CYP1A2 regulation.…”

Section: Discussionmentioning

confidence: 99%

A Dioxin-Responsive Enhancer 3′ of the HumanCYP1A2Gene

Okino

Quattrochi²,

Pookot³

et al. 2007

Mol Pharmacol

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The human CYP1A genes CYP1A1 and CYP1A2 are in a head-to-head orientation on chromosome 15. Both CYP1A genes and CYP1B1 are transcriptionally induced by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that binds 2, 3,7, dioxin). Although the TCDD-responsive enhancers for CYP1A1 and CYP1B1 are well characterized, a similar CYP1A2 enhancer has not been identified. In the human prostate cell line RWPE-1, CYP1A2 mRNA expression is dramatically induced by TCDD. Therefore, analysis of the native CYP1A2 gene in these cells can provide insight into its induction mechanism. To identify sites that may bind AhR on the CYP1A locus, we scanned 75 kilobases of chromosome 15 sequence for high-affinity AhR binding sites. We then analyzed most of the sites for TCDDinducible AhR interaction by chromatin immunoprecipitation.As expected, the CYP1A1 and CYP1B1 enhancers bind AhR in TCDD-treated cells. It is noteworthy that we identify a region 3Ј of CYP1A2 that also binds AhR in response to TCDD. We cannot detect AhR binding at other sites on the CYP1A locus. In vivo footprinting demonstrates that two AhR binding sites in the CYP1A2 3Ј region are occupied in TCDD-treated cells. Reporter-gene studies show that these sites confer TCDDresponsiveness to a heterologous promoter. AhR also binds to the CYP1A2 3Ј region in TCDD-treated LS180 cells but not in HepG2 and ND-1 cells. In the latter cell lines, the CYP1A2 3Ј region is extensively methylated. In summary, we identify a novel TCDD-responsive enhancer for CYP1A2. We were surprised to find that this enhancer is not conserved across species and is primarily human-specific.The CYP1 gene family, CYP1A1, CYP1A2, and CYP1B1, encode cytochrome P450s that metabolize a wide variety of structurally diverse chemicals and are implicated in both their detoxification and bioactivation into carcinogenic and toxic compounds. All members of the CYP1 gene family are transcriptionally induced by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that binds polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons with high affinity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), a notorious environmental contaminant, has the highest affinity for AhR and is the most potent inducer of the

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“…Likewise, in mice, the Cyp1a2 promoter is hypermethylated at birth when hepatic gene expression is low. Following birth, the CpG islands in the promoter become demethylated and mRNA levels of Cyp1a2 increase [43]. These studies suggest a role for both DNA methylation and histone modifications in the ontogenic regulation of Cyp enzymes.…”

Section: Phase I Metabolismmentioning

confidence: 99%

Establishment of Metabolism and Transport Pathways in the Rodent and Human Fetal Liver

Moscovitz

Aleksunes

2013

IJMS

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The ultimate fate of drugs and chemicals in the body is largely regulated by hepatic uptake, metabolism, and excretion. The liver acquires the functional ability to metabolize and transport chemicals during the perinatal period of development. Research using livers from fetal and juvenile rodents and humans has begun to reveal the timing, key enzymes and transporters, and regulatory factors that are responsible for the establishment of hepatic phase I and II metabolism as well as transport. The majority of this research has been limited to relative mRNA and protein quantification. However, the recent utilization of novel technology, such as RNA-Sequencing, and the improved availability and refinement of functional activity assays, has begun to provide more definitive information regarding the extent of hepatic drug disposition in the developing fetus. The goals of this review are to provide an overview of the early regulation of the major phase I and II enzymes and transporters in rodent and human livers and to highlight potential mechanisms that control the ontogeny of chemical metabolism and excretion pathways.

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CpG methylation of the mouse CYP1A2 promoter

Cited by 25 publications

References 35 publications

Epigenetic Regulation of ADME-Related Genes: Focus on Drug Metabolism and Transport

Epigenetic Regulation of ADME-Related Genes: Focus on Drug Metabolism and Transport

A Dioxin-Responsive Enhancer 3′ of the HumanCYP1A2Gene

Establishment of Metabolism and Transport Pathways in the Rodent and Human Fetal Liver

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