Coffee Induces Expression of Glucuronosyltransferases by the Aryl Hydrocarbon Receptor and Nrf2 in Liver and Stomach

Coffee is one of the most widely consumed beverages worldwide. Epidemiologic data indicate that coffee consumption protects against the progression of chronic liver disease and development of hepatocellular carcinoma and diabetes, but the mechanisms are not clear. UDP glucuronosyltransferases (UGT1A) are proteins with indirect antioxidant, cytoprotective, and genoprotective capabilities; we examined UGT1A regulation in response to coffee in cultured cells and mice.HepG2 and CaCo2 cells were incubated with regular, metal- or paper-filtered, decaffeinated, or instant coffee; green or black tea; cocoa; or metabolic products of caffeine. The effects of UGT1A regulation were investigated with reporter gene assays, immunoblot, TaqMan polymerase chain reaction, mutagenesis, and short interfering (si)RNA analyses. We also studied the effects of coffee in humanized transgenic mice that express human UGT1A.Incubation of cells with coffee induced transcription of UGT1A1 (5.4-fold), UGT1A3 (5.2-fold), UGT1A4 (4.8-fold), UGT1A7 (6.2-fold), UGT1A8 (5.2-fold), UGT1A9 (3.5-fold), and UGT1A10 (6.1-fold). Induction was independent of caffeine, methylxanthines, or the diterpenes cafestol and kahweol. Mutagenesis and short interfering RNA knockdown studies showed that UGT1A is regulated by the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid-related factor 2 (Nrf2) by cis-acting antioxidant and xenobiotic response elements (ARE/XRE). In transgenic UGT1A mice, administration of coffee resulted in a 10- and 14-fold induction of UGT1A transcription in liver and stomach, respectively.UGT1A genes are induced in vitro and in vivo by coffee, independent of caffeine content, cafestol, or kahweol. Coffee up-regulates glucuronidation by AhR signaling and Nrf2 binding to the ARE/XRE. Glucuronidation could mediate the protective and antioxidant effects of coffee.