Tissue‐specific Humanized Models Expressing Human UGT1A1

Abstract

The human UDP‐glucuronosyltransferases (UGTs) represent an important family of drug‐metabolizing enzymes. Among the nine UGT1A proteins, UGT1A1 has been the most extensively studied. UGT1A1 is the sole enzyme responsible for the glucuronidation of bilirubin and is involved in the conjugation of endogenous and many exogenous substances, including pharmaceutical drugs. Although the liver is considered a major organ for detoxification, intestinal UGT1A1 is also an important contributor for drug clearance. In order to investigate the role of both intestinal and hepatic human UGT1A1, we generated humanized strains that express only the UGT1A1 gene in either liver (hAlb1A1) or small intestine (hVil1A1). The two models were characterized by demonstrating hepatic and intestinal tissue specific expression of human UGT1A1. Body weight (BW) and total serum bilirubin (TSB) levels were monitored during different developmental stage. Both humanized models exhibited similar BW and normal TSB values in the adult stages. Differences between the two animal models were observed in the neonatal stage where hVil1A1 pups presented significantly lower TSB levels than hAlb1A1 mice, confirming that the intestinal expression of UGT1A1 is crucial in preventing bilirubin toxicity during development. Of importance is the finding that we have new humanized UGT1A1 mouse models to examine tissue‐specific glucuronidation. Given the importance of the intestinal tract in xenobiotic activation, metabolism and detoxification, we subsequently have isolated intestinal crypt organoids from these same animal models. The use of these in vivo models and their in vitro complementary primary cell models provide important tools for studying intestinal and hepatic toxicity of drugs and environmental toxicants that are metabolized by UGT1A1.Support or Funding InformationSupported by National Institutes of Health grants GM126074 and ES010337