Functions and transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases (UGTs): mechanisms responsible for interindividual variation of UGT levels.

Ten out of 19 UDP-glucuronosyltransferases (UGTs) are substantially expressed in adult human liver (>1% of total UGTs); 5 UGT1 isoforms (UGT1A1, 1A3, 1A4, 1A6 and 1A9) and 5 UGT2 family members (UGT2B4, 2B7, 2B10, 2B15 and 2B17) (Izukawa et al. [11]). Surprisingly, UGT2B4 and UGT2B10 mRNA were found to be abundant in human liver suggesting an underestimated role of the liver in detoxification of their major substrates, bile acids and eicosanoids. Among factors responsible for high interindividual variation of hepatic UGT levels (genetic diversity including polymorphisms and splice variants, regulation by liver-enriched transcription factors such as HNF1 and HNF4, and ligand-activated transcription factors) nuclear receptors (PXR, CAR, PPARalpha, etc.), and the Ah receptor are discussed. Unraveling the mechanisms responsible for interindividual variation of UGT expression will be beneficial for drug therapy but still remains a major challenge. Copyright 2010 Elsevier Inc. All rights reserved.