Abstract

The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major Phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty) and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 and PAPSS1 were increased in NASH (not fatty/cirrhosis) only. UGT1A9, 1A6 and SULT1A1, 2A1 protein levels were decreased in NASH; however SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared to normal samples, but then decreased in NASH compared to steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD.