The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs.[4] This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands, instead of relying on gene variants for wider specificity.[4] 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.[5] This change in consequence contributes to an increased human defense against cholestasis.[5]