CYP3A regulation: From pharmacology to nuclear receptors

Among the human liver cytochrome P450s (P450s), a family of microsomal hemo proteins responsible for catalyzing the oxidative metabolism of clinically used drugs and environmental chemicals, attention has been focused on CYP3A , a form that is the most abundant and is inducible by many of its substrat es. From early pharmacological studies that demonstrated induction of CYP3A by glucocorticoids and, paradoxically, by antiglucocorticoids, the existen ce of a nonclassical glucocorticoid receptor mechanism was inferred and pro mpted research that culminated in the identification of a unique member of the nuclear receptor family, the pregnane X receptor (PXR; NR112). It has b ecome increasingly evident that PXR as well as other nuclear receptors medi ate CYP3A induction in a unique and complex manner including inducibility b y structurally diverse compounds and striking interspecies differences in i nduction profiles. Future understanding of the role of nuclear receptors in regulating expression of CYP3A and other genes of the P450 family offers a n exciting promise of further defining the physiologic function and interin dividual differences of CYP3A in health and disease.