Evaluation of two novel models to examine the human xenobiotic-response: An immortalized human hepatocyte cell line and a 'humanized' pregnane X receptor mouse

Certain xenobiotics have been shown to increase their own clearance from the human body through induction of specific cytochrome P450s (CYPs) in liver at the level of transcription. This type of CYP induction causes clinically relevant drug-drug interactions. The standard model for evaluating CYP induction is primary cultures of human hepatocytes (PCHH), but their limitations has led to a search for new models. An immortalized human hepatocyte cell line, Fa2N-4, offers one alternative. Genetically engineered and "humanized" animal models represent another. The induction of specific CYPs (CYP3A4, CYP1A2, CYP2B6, and CYP2C9) in Fa2N-4 and PCHH was compared using real-time quantitative PCR. Additionally, a 'humanized' mouse model was developed and validated. The data presented in this thesis suggest that the Fa2N-4 cell line and the 'humanized' mouse represent possible alternative model systems that may be of use in screening for the induction of CYPs in pre-clinical drug development.