Disease models

Mouse intestinal organoids could be used to model intestinal drug metabolism and toxicity. The organoids were generated by treating primary mouse crypt cells isolated from the small intestine with a cocktail of mouse epidermal growth factor (EGF), noggin (NOG) and R-Spondin 1(RSPO1). In the organoids, tool compounds that agonized nuclear receptors -- including aryl hydrocarbon receptor (AHR), constitutive androstane receptor (NR1I3; CAR), liver X receptor (LXR), pregnane X receptor (PXR) and peroxisome proliferation activated receptor α (PPARα) -- recapitulated the high levels of cytochrome P450 drug-metabolizing enzymes and the ATP-binding cassette sub-family A member 1 (ABCA1) drug transporter observed in the intestines of mice treated with the agonists. In the organoids treated with irinotecan, knockout of the metabolic enzyme UDP glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) increased apoptosis compared with normal UGT1A1 expression. Next steps could include using the organoids to test the metabolism and toxicity of other drugs...