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

  title={The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability},
  author={Huan Qiu and Marianne Mathaes and Sebastian Nestler and Christopher Bengel and Dieudonn{\'e} Nem and Ute Gödtel-Armbrust and Thomas Lang and Stefan Taudien and Oliver Burk and Leszek Wojnowski},
  journal={Pharmacogenetics and Genomics},
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… 

Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4

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.

DNA elements for constitutive androstane receptor- and pregnane X receptor-mediated regulation of bovine CYP3A28 gene

Present results point to species-differences in CYP3A regulation and the complexity of bovine CYP 3A28 regulatory elements, but further confirmatory studies are needed.

Independent losses of a xenobiotic receptor across teleost evolution

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.

African variation at Cytochrome P450 genes

  • R. K. Bains
  • Biology, Medicine
    Evolution, medicine, and public health
  • 2013
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.

Evolutionary aspects and the implications for the treatment of infectious diseases

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 and the known associations with sub-optimal clinical outcomes in the treatment of infectious diseases.

Evolutionary history and functional characterization of the amphibian xenosensor CAR.

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.

Genetic polymorphisms affecting drug metabolism: recent advances and clinical aspects.

  • A. Daly
  • Biology, Medicine
    Advances in pharmacology
  • 2012



Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene.

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.

Identification of a novel polymorphic enhancer of the human CYP3A4 gene.

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.

CYP3 phylogenomics: evidence for positive selection of CYP3A4 and CYP3A7

CYP3A7 and CYP3A4 may have acquired catalytic functions especially important for the evolution of hominoids and humans, respectively.

Clinical implications of CYP3A polymorphisms

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.

The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module.

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.

Molecular Mechanisms of Polymorphic CYP3A7 Expression in Adult Human Liver and Intestine*

It is concluded that the presence of the ER6 motif of CYP3A4mediates the high expression of CYp3A7 in subjects carrying CYP 3A7*1C.

CYP3A variation and the evolution of salt-sensitivity variants.

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.

Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression

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.

Molecular Mechanism of Basal CYP3A4 Regulation by Hepatocyte Nuclear Factor 4α: Evidence for Direct Regulation in the Intestine

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.