Lessons from the CYP3A4 Promoter

Schuetz, Erin G.

doi:10.1124/mol.65.2.279

Cited by 43 publications

(32 citation statements)

References 41 publications

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“…Clinically, only CYP3A4*22 has consistently been associated with reduced catalytic activity (Elens et al, 2011;Wang et al, 2011), however, it is unlikely to be a major determinant of CYP3A4 activity in the broader context, with a minor allele frequency of just 3%-8% in the white population. The lack of commonly occurring genetic variation in the CYP3A4 gene has led to the hypothesis that variability in factors responsible for regulating constitutive and inducible expression of CYP3A4 is responsible for interindividual variability (Schuetz, 2004). Polymorphisms in liver-enriched transcription factors, including FOXA2 (HNF3b), HNF4A, FOXA3 (HNF3g), NR1I2 (pregnane, PXR), ARNT, GR, PGRMC2, and PPARA, as well as polymorphisms in transporters (e.g., ABCB1, SLCO1B3), have been investigated for their effects on CYP3A4 expression and activity (Franke et al, 2008;Lamba et al, 2010;Klein et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Vyhlidal

et al. 2016

Drug Metabolism and Disposition

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Members of the human CYP3A family of metabolizing enzymes exhibit developmental changes in expression whereby CYP3A7 is expressed in fetal tissues, followed by a transition to expression of CYP3A4 in the first months of life. Despite knowledge about the general pattern of CYP3A activity in human development, the mechanisms that regulate developmental expression remain poorly understood. Epigenetic changes, including cytosine methylation, have been suggested to play a role in the regulation of CYP3A expression. The objective of this study was to investigate changes in cytosine methylation of the CYP3A4 and CYP3A7 genes in human pediatric and prenatal livers. The methylation status of cytosinephospho-guanine dinucleotides was determined in 16 pediatric liver samples using methyl-seq and confirmed by bisulfite sequencing of 48 pediatric and 34 prenatal liver samples. Samples were separated by age into five groups (prenatal, < 1 year of age, 1.8-6 years, 7-11 years, and 12-17 years). Methyl-seq anaylsis revealed that cytosines in the proximal promoter of CYP3A7 are hypomethylated in neonates compared with adolescents (P < 0.001). In contrast, a cytosine 383 base pair upstream of CYP3A4 is hypermethylated in liver samples from neonates compared with adolescents (P = 0.00001). Developmental changes in methylation of cytosines in the proximal promoters of CYP3A4 and CYP3A7 in pediatric livers were confirmed by bisulfite sequencing. In addition, the methylation status of cytosine in the CYP3A4 and CYP3A7 proximal promoters correlated with changes in developmental expression of mRNA for the two enzymes.

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Section: Introductionmentioning

confidence: 99%

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Vyhlidal

et al. 2016

Drug Metabolism and Disposition

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“…Variability in the PKs of anticancer agents can be attributed to a number of factors including comedications, environmental factors, genetic polymorphisms and certain disease states. These factors can have an impact on drug disposition, resulting in either ineffective drug doses or excessive toxicity (Thummel and Wilkinson, 1998;Schuetz, 2004). This concept is supported by a study demonstrating that reductions in CYP3A4 activity in patients with advanced cancer were correlated to an increased plasma concentration of the inflammatory mediators interleukin (IL-)6 and C-reactive protein (CRP) (Rivory et al, 2002;Slaviero et al, 2003).…”

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confidence: 96%

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

et al. 2007

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There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.

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“…CYP3A4 is one of the predominant P450 isoforms expressed in adult liver. It catalyzes the metabolism of more than 50% of clinically used drugs (Schuetz, 2004). Induction of CYP3A4 can result in clinically significant drug-drug interactions or autoinduction (Lin, 2006) and, therefore, is a major concern for the pharmaceutical industry.…”

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confidence: 99%

Comparison of Immortalized Fa2N-4 Cells and Human Hepatocytes as in Vitro Models for Cytochrome P450 Induction

Hariparsad¹,

Carr²,

Evers³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Fa2N-4 cells have been proposed as a tool to identify CYP3A4 inducers. To evaluate whether Fa2N-4 cells are a reliable surrogate for cryopreserved human hepatocytes, we assessed the basal mRNA expression of 64 drug disposition genes in Fa2N-4 cells. Significant differences were found in the expression of major drugmetabolizing enzymes, nuclear receptors, and transporters between both cell types. Importantly, the expression of constitutive androstane receptor (CAR) and several hepatic uptake transporters was significantly lower (>50-fold) in Fa2N-4 cells, whereas the expression of pregnane X-receptor (PXR) and aryl hydrocarbon receptor (

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Lessons from the CYP3A4 Promoter

Cited by 43 publications

References 41 publications

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

Comparison of Immortalized Fa2N-4 Cells and Human Hepatocytes as in Vitro Models for Cytochrome P450 Induction

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