Molecular mechanisms of cytochrome p450 induction: potential for drug-drug interactions.
The human liver cytochromes P450 (CYP P450s) are superfamily of hemoproteins responsible for catalyzing the oxidative metabolism of drugs and xenobiotics entering human body. Drug-drug/xenobiotic interactions are a major cause of therapeutic failures and adverse events. The concomitant administration of inducers with other drugs that are metabolized by CYP450 can result in their altered metabolism in the gastrointestinal tract and/ or liver. The clinical importance of such interactions includes auto induction leading to suboptimal or failed treatment. It is a major concern for the drug companies while developing new drugs. The present understanding of the mechanisms of induction of CYP P450s enzymes and their regulation has made considerable progress during last few years. However there are still gaps in our understanding on molecular aspects of CYP enzymes. Therefore, it remains the subject of intense scientific research to ascertain their in vivo function, and also better understand how the expression of CYP enzymes is regulated at the molecular level. This review analyzes and presents recent findings and concepts on xenosensors and their target genes. Emphasis is given to the molecular mechanisms and signaling pathways of CYP P450 mediated induction by xenobiotics and their potential for drug-drug interactions.
Jana
Snehasis
S
Metabolism and Pharmacokinetics Division, Ranbaxy Research Laboratories, Plot-20, Sector-18, Udyog Vihar, Industrial Area, Gurgaon, Haryana -122015, India.
Paliwal
Jyoti
J
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology*
D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System