Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man.
1. The importance of CYP3A enzymes in drug metabolism and toxicology has yielded a wealth of information on the structure, function and regulation of this subfamily and recent research emphasis has been placed on the human forms, namely CYP3A4, CYP3A5, CYP3A7 and CYP3A43. 2. The current review will focus on the receptor-dependency of CYP3A regulation and includes consideration of the regulatory roles of the glucocorticoid (GR), pregnane X (PXR) and constitutive androstane (CAR) receptors. 3. Emphasis has been placed on the topics of expression and substrate specificity, assessment of induction, species differences in induction, CYP3A promoter sequences and regulation of gene expression, structural and functional aspects of receptor-mediated, CYP3A gene activation, receptor variants and interindividual variation in human CYP3A expression, the latter encompassing environmental, physiological and genetic aspects. 4. An outline of future research needs will be discussed in the context of receptor-mediated molecular mechanisms of CYP3A gene regulation and the impact on interindividual variations in CYP3A expression. 5. Taken collectively, this review highlights the importance of understanding the molecular mechanisms of CYP3A induction as a means of rationalizing human responses to many clinically used drugs, in addition to providing a mechanistically coherent platform to understand and predict interindividual variations in response and drug-drug interactions.
Gibson
G G
GG
Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, UK. g.gibson@surrey.ac.uk
Plant
N J
NJ
Swales
K E
KE
Ayrton
A
A
El-Sankary
W
W
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics*; D011955:Receptors, Drug / Q000187:drug effects*; D013045:Species Specificity; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects*
D007527:Isoenzymes; D011955:Receptors, Drug; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating