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The small intestine (SI) is the first site for metabolism of orally ingested xenobiotics, including nutrients, toxicants, and therapeutic agents.Among the many biotransformation enzymes expressed in the SI, the cytochrome P450 (P450) monooxygenases are the greatest contributors to the catalysis of biotransformation reactions.In this presentation, I will describe an intestinal epithelium (IE)-specific P450 reductase gene (Cpr) knockout mouse model (designated IE-Cpr-null), which has been proven to be a powerful tool for direct determination of the in vivo functions of all microsomal P450 enzymes in intestinal epithelial enterocytes.In the IE-Cpr-null mice, the expression of CPR, a protein essential for the functioning of all microsomal P450 enzymes, was abolished specifically in the IE cells.Through the use of this novel mouse model, we have shown that intestinal microsomal P450 enzymes play important roles in controlling the rates of first-pass clearance, metabolic disposition, systemic bioavailability, and target tissue toxicity of many oral drugs.We have also discovered roles of microsomal P450 enzymes in the modulation of intestinal inflammation and immunity and in colon carcinogen metabolism and activation.