The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability

@article{Qiu2010TheUC,
  title={The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability},
  author={H. Qiu and Marianne Mathaes and S. Nestler and Christopher Bengel and Dieudonn{\'e} Nem and U. Gödtel-Armbrust and T. Lang and S. Taudien and O. Burk and L. Wojnowski},
  journal={Pharmacogenetics and Genomics},
  year={2010},
  volume={20},
  pages={167-178}
}
Objective The individually variable and unpredictable expression of CYP3A4 compromises therapies with 50% of contemporary drugs. Gene variants explain only a fraction of this variability. Methods We investigated the evolution of CYP3A4 transcriptional regulation by nuclear receptors such as the xenobiotics sensors PXR and CAR. Results The combination of a proximal ER6 element with XREM and CLEM represents the original scheme of CYP3A regulation by nuclear receptors in placental mammals. Among… Expand
Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4
TLDR
It is demonstrated that the CYP3A5 expression in these organs is non-inducible and independent from PXR, and the loss of a suppressing yin yang 1 (YY1)-binding site from the CYp3A 5 promoter which occurred in haplorrhine primates during primate evolution is described, a first description of uncoupling induction from constitutive expression for a major detoxifying enzyme. Expand
DNA elements for constitutive androstane receptor- and pregnane X receptor-mediated regulation of bovine CYP3A28 gene
TLDR
Present results point to species-differences in CYP3A regulation and the complexity of bovine CYP 3A28 regulatory elements, but further confirmatory studies are needed. Expand
Independent losses of a xenobiotic receptor across teleost evolution
TLDR
It is shown that the xenosensor pregnane X receptor (Pxr, Nr1i2) is absent in more than half of teleost fish species, and it is suggested that the aryl hydrocarbon receptor (Ahr) have evolved an extended regulatory role by governing the expression of certain Pxr target genes, such as cyp3a, in Atlantic cod. Expand
Epigenetic Regulation of Cytochrome P450 Enzymes and Clinical Implication.
TLDR
An up-to-date summary of epigenetic studies on human CYPs is provided, and how such information could be integrated with clinical application is discussed. Expand
African variation at Cytochrome P450 genes
  • R. K. Bains
  • Medicine
  • Evolution, medicine, and public health
  • 2013
TLDR
The potential for evolutionary approaches in the study of CYP450 variation is discussed to examine their potential in preventative medicine and intervention strategies within Africa to examine how these changes influence adverse drug reactions. Expand
A CAR-responsive enhancer element locating approximately 31 kb upstream in the 5'-flanking region of rat cytochrome P450 (CYP) 3A1 gene.
TLDR
DR4 and/or DR2 motifs being primarily responsible and HNF1 being synergistically functioning elements for the rCAR-mediated transcription of CYP3A1 are concluded. Expand
Histone deacetylase 1 is required for Carbamazepine-induced CYP3A4 expression.
TLDR
Data, for the first time, indicate that HDAC1, is required for the CBZ-induced CYP3A4 expression, which influences the pharmaceutical profiles of the co-administrated drugs. Expand
Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation.
TLDR
Recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s are reviewed. Expand
Evolutionary aspects and the implications for the treatment of infectious diseases
The genomics revolution has provided a plethora of data from many previously uncharacterized populations. The increase in the amount of genetic data has improved our understanding of why individualsExpand
Evolutionary history and functional characterization of the amphibian xenosensor CAR.
TLDR
Xenopus CAR is a first reported amphibian xenosensor, which opens the way to toxicogenomic and bioaugmentation studies in this critically endangered taxon of land vertebrates and provides a comprehensive reconstruction of the evolutionary history of the NR1I subfamily of nuclear receptors. Expand
...
1
2
3
...

References

SHOWING 1-10 OF 47 REFERENCES
Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene.
TLDR
The identification of a new member of the CYP3A family and the characterization of the full CYP 3A locus will aid efforts to identify the genetic variants underlying its variable expression, which will lead to a better optimization of therapies involving the numerous substrates of CYP2A proteins. Expand
Identification of a novel polymorphic enhancer of the human CYP3A4 gene.
TLDR
The results suggest that CLEM4 is a constitutive enhancer of the CYP3A4 gene in the liver and that -11,129_-11,128insTGT may at least partly contribute to the interindividual variability of CYP 3A4 expression. Expand
CYP3 phylogenomics: evidence for positive selection of CYP3A4 and CYP3A7
TLDR
CYP3A7 and CYP3A4 may have acquired catalytic functions especially important for the evolution of hominoids and humans, respectively. Expand
Clinical implications of CYP3A polymorphisms
TLDR
The most important underlying problems are the continuing absence of activity markers specific for CYP3A4 and the strong contribution of nongenetic factors to CYP2A variability and the detection of clinical effects of CYP 3A gene variants will be difficult. Expand
Genetic contribution to variable human CYP3A-mediated metabolism.
TLDR
The human CYP3A subfamily plays a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme and may be implicated in disease risk and the metabolism of endogenous steroids or xenobiotics in these tissues. Expand
The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module.
TLDR
The results provide evidence for the existence of a potent enhancer module, 8 kb distal to the transcription start point, which mediates the transcriptional induction of CYP3A4 by activators of hPXR and demonstrate cooperativity between elements within the distal enhancer region and cis-acting elements in the proximal promoter of CYp3A 4. Expand
Molecular Mechanisms of Polymorphic CYP3A7 Expression in Adult Human Liver and Intestine*
TLDR
It is concluded that the presence of the ER6 motif of CYP3A4mediates the high expression of CYp3A7 in subjects carrying CYP 3A7*1C. Expand
CYP3A variation and the evolution of salt-sensitivity variants.
TLDR
Results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude. Expand
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression
TLDR
CYP3A5 was more frequently expressed in livers of African Americans than in those of Caucasians, and may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines. Expand
Molecular Mechanism of Basal CYP3A4 Regulation by Hepatocyte Nuclear Factor 4α: Evidence for Direct Regulation in the Intestine
TLDR
A molecular mechanism of direct regulation of CYP3A4 by HNF4α is elucidated, which is probably specific for the intestine and suggested by the presence of a binding activity in small intestine similar to that in LS174T cells. Expand
...
1
2
3
4
5
...