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UNIVERSITY OF MALTA RESEARCH SEMINARS Abstract form Title: Receptor-mediated cytochrome P450 induction - pharmacological and toxicological implications Presenter: Professor Gabrielle M Hawksworth Contact address: Department of Medicine and Therapeutics, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, AB25 2ZD Tel: + 44 1224 552487 Fax: + 44 1224 554761 Email: [email protected] Presentation date: 14 November 2005 Abstract (approximately 200-250 words) Cytochrome P450 (CYP) is the main hepatic enzyme responsible for oxidative drug metabolism and hence interindividual variation in response to drugs. CYPs belong to a multigene family, with individual isoforms having different substrate specificities, species differences, inducibility and regulation. It is now routine at an early stage in drug discovery to determine the human CYP isoform(s) responsible for the major oxidative pathways in the metabolism of a new chemical entity (NCE). The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are implicated in the regulation of CYP3A and CYP2B respectively, although there is cross talk between these receptors. These nuclear receptors play an important role in determining species differences in CYP3A- and CYP2Bdependent metabolism. Clinically significant drug-drug interactions involving transport proteins have also been demonstrated and we have shown that PXR ligands and CAR ligands can induce Oatp1a4, but not Oatp1a1, expression in vivo and in vitro in the rat, provided that hepatocytes are cultured in a ‘Matrigel’ or a collagen sandwich configuration. Primary rat and human hepatocytes cultures in a sandwich configuration form extensive canalicular networks and express functional transport proteins on appropriate membrane domains, which provides the opportunity to investigate drug substrate specificity for these transporters and inducibility of the transporters.
