[The role of nuclear receptors in cytochrome P-450 induction by xenochemicals].
This review summarizes recent findings indicating that members of the orphan nuclear receptor superfamily regulate the synthesis of their CYP genes which code CYP enzymes involved in metabolism of endogenous and exogenous compounds. The foreign compounds metabolism and the role played by individual cytochrome P450 (CYP) enzymes in the activation and detoxification of xenochemicals prevalent in the environment are important areas of molecular pharmacology and toxicology. The advances in our understanding of the mechanisms through which foreign chemicals impact on these CYP-dependent metabolic processes have been made during the past years. Role for three "orphan" nuclear receptor superfamily members, designated CAR (constitutive androstane receptor), PXR/SXR (pregnelone X receptor) and PPAR (peroxisome proliferator activated receptor), in respectively mediating the induction of hepatic CYPs belonging to families CYP2, CYP3, and CYP4 has now been established. The CYP gene products such as CYP3A, CYP2B and PPAR are essential for metabolism of endogenous steroid hormones, fatty acids and various xenobiotics including drugs. Unexpectedly, it has been shown that SXR, which regulates CYP3A, can also regulate CYP2B via recognition of the phenobarbital response element (PBRE). In a type of functionally symmetry, orphan receptor CAR was found to activate CYP3A through SXR/PXR response element. Indeed, SXR/PXR binds to inverted (IR-6) and direct (DR-4) response element localized to regulatory DNA regions of human CYP3A4 and rat CYP3A23 genes, respectively. These observations provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics as well as the propensity for drug-drug interactions. In addition, both endogenous and exogenous ligands which act as activators of nuclear receptors can result in disruption of cellular homeostasis.
Palut
Danuta
D
Zakład Toksykologii Srodowiskowei, Państwowy Zakład Higieny, 00-791 Warszawa.
Kostka
Grazyna
G
Struciński
Paweł
P
D000818:Animals; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism / Q000494:pharmacology
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System