BioCentury
ARTICLE | Distillery Techniques

Disease models

May 31, 2017 1:21 PM UTC

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...