Regulation of sulfotransferase and UDP-glucuronosyltransferase gene expression by the PPARs

Abstract

During phase II metabolism, a substrate is rendered more hydrophilic through the covalent attachment of an endogenous molecule. The cytosolic sulfotransferase (SULT) and UDP-glucuronosyltransferase (UGT) families of enzymes account for the majority of phase II metabolism in humans and animals. In general, phase II metabolism is considered to be a detoxication process, as sulfate and glucuronide conjugates are more amenable to excretion and elimination than are the parent substrates. However, certain products of phase II metabolism (e.g., unstable sulfate conjugates) are genotoxic. Members of the nuclear receptor superfamily are particularly important regulators of SULT and UGT gene transcription. In metabolically active tissues, increasing evidence supports a major role for lipid-sensing transcription factors, such as peroxisome proliferator-activated receptors (PPARs), in the regulation of rodent and human SULT and UGT gene expression. This review summarizes current information regarding the regulation of these two major classes of phase II metabolizing enzyme by PPARs.

Figure 1

Example reactions catalyzed by PPAR-regulated SULT and UGT enzymes. The upper panel shows the SULT2A1- and SULT2B1b-catalyzed 3-sulfonation of the prototype substrates, dehydroepiandrosterone and cholesterol, respectively. Human SULT2A1 is transcriptionally regulated by PPARα in human hepatocytes, while SULT2B1b is regulated by PPARα, PPARδ and PPARγ in keratinocytes. The lower panel shows the glucuronidation of bilirubin, p-nitrophenol and hyodeoxycholic acid, which are prototype substrates for UGT1A1, UGT1A6, and UGT2B4, respectively. UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B4 have all been identified as PPAR target genes. PAPS, 3′-phosphoadenosine-5′-phosphosulfate; UDP-GA, uridine-5′-diphospho-α-D-glucuronic acid.

Figure 2

Regulation of SULT and UGT gene transcription by PPARα. The PPARα and RXR nuclear receptors are each depicted as a zinc module-containing DNA-binding domain (rectangle) that is joined to a ligand-binding domain (LBD, triangle) through a hinge region. PPARα and RXR bind as a heterodimer to a peroxisome proliferator response element (PPRE) in the regulatory region of a target gene. The consensus PPRE is a nuclear receptor hexamer motif (i.e., (A/G)G(G/T)TCA) in a DR-1 configuration (direct repeat with one intervening nucleotide, N). Binding of an agonist to the LBD of PPARα (e.g., chemical structure for the potent PPARα agonist, ciprofibrate, is shown) evokes a conformational change in the receptor that results in coactivator recruitment and increased target gene transcription. In contrast to its silent role in partnership with some nuclear receptors, RXR functions as an active partner with the PPARs, whereby binding of an agonist to the LBD of RXR (e.g., chemical structure for the prototype RXR ligand, 9-cis-retinoic acid, is shown) activates target gene transcription and enhances PPAR ligand-activated transcription. The locations of functional PPREs that have been identified in the 5′-flanking regions of the human SULT2A1, UGT1A1, UGT1A3, UGT1A6, UGT1A9, and UGT2B4 genes are shown (positions are relative to the transcription start site).

Figure 3

Representation of keratinocyte differentiation and role of SULT2B1b-mediated cholesterol sulfonation. During formation of the epidermis, replicating basal keratinocytes give rise to progeny that move progressively upwards and pass through several histologically distinct strata. During this process, SULT2B1b expression becomes activated at approximately the level of the stratum granulosum. SULT2B1b-catalyzed cholesterol sulfonation produces cholesterol 3-sulfate that, in addition to its role as a lipid component of the outer barrier, functions as a signaling molecule that activates PKCη and possibly RORα. These signaling events result in the induction of proteins that are involved in formation of the barrier. PPARα, PPARδ, PPARγ, and LXR have all been reported to positively regulate SULT2B1b expression in cultured keratinocytes.