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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 responsive to PXR and CAR increased in primate CYP3A4 orthologs, which led to enhanced CYP3A4 inducibility. Additions to the other primate CYP3A genes were more restricted and specific, as exemplified by a CYP3A5 DR4 site responsive to CAR, but not to PXR. All these changes resulted in human CYP3A4 having a much more complex upstream regulatory region in comparison to its paralogs.Instead of gene variants, the intraindividual CYP3A4 expression variability in humans may be primarily caused by particular sensitivity of this gene to endogenous and exogenous PXR and CAR ligands conferred by the unique complexity of its upstream regulatory region.