Figure 7.

The hepatic clearance of bile salts and other organic solutes is determined by four steps or phases; Phase 0, hepatic uptake; Phase I, hydroxylation by cytochrome 3A and other CYP450s; Phase II, conjugation reactions with glucuronides, glutathione, sulfates, or acetates; and Phase III, export from the liver by adenosine triphosphate-dependent ATP-binding cassette (ABC) transporters. The figure also shows the coordinated ligand-activated regulation of gene expression that determines the hepatic clearance of bile salts, bilirubin, and xenobiotics. Some of the major nuclear receptors that regulate the expression of these key genes are shown. Unless otherwise indicated by ↓ or – symbols, these ligands stimulate gene expression. Normally, many of these nuclear receptors form heterodimeric complexes with the retinoid X receptor (RXR). This complex then binds to specific response elements in the gene promoter. Other nuclear receptors such as short heterodimeric protein-1, fetal transcription factor (FTF), and hepatocyte nuclear factor 1 (HNF-1) do not form heterodimers with RXR and do not have specific ligands. Reprinted, with permission, from Ref. (78).