Editing CYP3A4 (section)

== Evolution ==
The ''CYP3A4'' gene exhibits a much more complicated upstream regulatory region in comparison with its [[Homology (biology)#Paralogy|paralogs]].<ref name="Qiu_2010">{{cite journal | vauthors = Qiu H, Mathäs M, Nestler S, Bengel C, Nem D, Gödtel-Armbrust U, Lang T, Taudien S, Burk O, Wojnowski L | s2cid = 205602787 | title = The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 3 | pages = 167–78 | date = March 2010 | pmid = 20147837 | doi = 10.1097/FPC.0b013e328336bbeb }}</ref> This increased complexity renders the ''CYP3A4'' gene more sensitive to endogenous and exogenous [[pregnane X receptor]] (PXR) and [[constitutive androstane receptor]] (CAR) ligands, instead of relying on gene variants for wider specificity.<ref name="Qiu_2010" /> [[Chimpanzee]] and human CYP3A4 are highly conserved in metabolism of many [[ligands]], although four amino acids positively selected in humans led to a 5-fold [[benzylation]] of [[7-BFC]] in the presence of the [[hepatotoxic]] secondary [[bile acid]] [[lithocholic acid]].<ref name="Kumar_2009">{{cite journal | vauthors = Kumar S, Qiu H, Oezguen N, Herlyn H, Halpert JR, Wojnowski L | title = Ligand diversity of human and chimpanzee CYP3A4: activation of human CYP3A4 by lithocholic acid results from positive selection | journal = Drug Metabolism and Disposition | volume = 37 | issue = 6 | pages = 1328–33 | date = June 2009 | pmid = 19299527 | pmc = 2683693 | doi = 10.1124/dmd.108.024372 }}</ref> This change in consequence contributes to an increased human defense against [[cholestasis]].<ref name="Kumar_2009" />