0000000000587222
AUTHOR
Stefan Taudien
showing 2 related works from this author
CYP3 phylogenomics: evidence for positive selection of CYP3A4 and CYP3A7.
2008
CYP3A metabolizes 50% of currently prescribed drugs and is frequently involved in clinically relevant drug interactions. The understanding of roles and regulations of the individual CYP3A genes in pharmacology and physiology is incomplete.Using genomic sequences from 16 species we investigated the evolution of CYP3 genomic loci over a period of 450 million years.CYP3A genes in amniota evolved from two ancestral CYP3A genes. Upon the emergence of eutherian mammals, one of them was lost, whereas, the other acquired a novel genomic environment owing to translocation. In primates, CYP3A underwent rapid evolutionary changes involving multiple gene duplications, deletions, pseudogenizations, and …
The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability.
2010
The individually variable and unpredictable expression of CYP3A4 compromises therapies with 50% of contemporary drugs. Gene variants explain only a fraction of this variability.We investigated the evolution of CYP3A4 transcriptional regulation by nuclear receptors such as the xenobiotics sensors PXR and CAR.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 human CYP3A genes, this scheme is retained only in CYP3A4, whereas non-CYP3A4 genes lost these elements to a variable extent during primate evolution. In parallel, the number of elements outside XREM and CLEM potentially responsi…