MP7 Toxicogenomics in Environmental Studies
Monday, 14 November 2005: 8:00 AM - 5:30 PM in Exhibit Hall

(PLA-1117-724099) Regulation of CYP enzymes and Drug Transporters by Drugs and Environmental Chemicals.

PLANT, N¹, AL-SALMAN, F², GIBSON, G³, ¹ University of Surrey, Guildford, U.K² University of Surrey, Guildford, U.K³ University of Surrey, Guildford, U.K

ABSTRACT- The body is constantly exposed to many different external chemicals (xenobiotics), be they environmental toxins or therapeutic medicines. Cytochrome P450 enzymes and drug transporters form part of the core protection system for the body, regulating entry of xenobiotics, and increasing clearance rates of chemicals that do enter the body. It is therefore important to know how these systems will respond to novel chemicals, with human cell lines being commonly used in such drug metabolism studies. In this study we have determined the transcript levels for several cytochrome P450s or drug transporter from human liver (Huh7), intestine (CaCo-2) and lung (A549) cell lines, and compared them to adult and foetal levels in the respective tissues: Basal expression of the selected CYP genes and drug transporters is significantly lower in these cell lines than in either adult or foetal primary tissue. We have also examined the effect of xenobiotic exposure on the expression of these transcripts, showing that whereas some cell lines have maintained their ability to show genome-base activations of gene expression, others are refractory , a fact that has important implications for drug studies carried out in these cell lines. Finally, we have examined how two of these genes, CYP3A4 and MDR1, are regulated in different tissues and cell types. Current evidence suggests that in certain tissues these genes show positive coordination of their response to xenobiotic exposure, whereas in other negative or no coordination is seen. Using reporter gene constructs for the proximal promoters of these two genes we are examining the molecular mechanisms underlying these complex responses to chemical exposure. Such work will help improve prediction of body responses to xenobiotic exposure, as well as increase the accuracy of current risk assessment methodologies.

Key words: CYP, Cytochrome P450, MDR1, multidrug resistance gene