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.
Phase II, or conjugative, metabolism is defined as the covalent attachment of an endogenous molecule to a functional group on a substrate molecule. Although a substrate containing a suitable functional group can directly undergo phase II metabolism, conjugation often occurs subsequent to a phase I reaction (e.g., catalyzed by a cytochrome P450), during which the functional group is added to the substrate. The conjugating moiety is most often a sulfonate or glucuronate group, although other conjugating moieties include glutathione, glycine, acetate, and the methyl group. Phase II metabolism usually increases the hydrophilicity of the substrate molecule, which facilitates transport and elimination of the product. Phase II sulfonation and glucuronidation reactions are catalyzed by the cytosolic sulfotransferase (SULT) and the UDP-glucuronosyltransferase (UGT) families of enzymes, respectively, (Figure
The PPAR nuclear receptor network represents a central determinant of cellular energy balance. In heterodimeric partnership with the retinoid X receptor (RXR), PPAR forms a ligand-activated nuclear receptor transcription factor that is capable of integrating the expression of a wide spectrum of target genes involved in cellular lipid metabolism, energy homeostasis, and inflammation (Figure
Sulfonation reactions are catalyzed by two distinct families of enzymes, the cytosolic SULTs and the membrane-bound sulfotransferases. Of these, only the SULTs participate in phase II drug metabolism; the membrane-bound sulfotransferases catalyze the sulfonation of proteins and complex carbohydrates [
Like other classes of xenobiotic-metabolizing enzymes, the SULTs exist as a superfamily of related proteins with each enzyme exhibiting a characteristic expression pattern and substrate specificity profile. The cytosolic SULTs are categorized into two major groups, the arylsulfotransferases (SULT1 family) and the hydroxysteroid sulfotransferases (SULT2 family) [
The SULT2 family is divided into two subfamilies, SULT2A and SULT2B. In general, these SULTs most effectively metabolize molecules containing a steroid or sterol nucleus (e.g., dehydroepiandrosterone (DHEA), pregnenolone, cholesterol, and bile acids) [
The SULT2B subfamily consists of two gene products, SULT2B1a and SULT2B1b, that are transcribed from the same gene locus through the utilization of different promoters and incorporation of different first exons [
By comparison to SULT2B1b, SULT2B1a has minimal activity toward cholesterol but readily catalyzes the sulfonation of pregnenolone [
In addition to the major SULT1 and SULT2 enzymes, SULT3A1, SULT3A2, SULT4A1, SULT5A1, and SULT6B1 have been described [
A comprehensive survey of SULT regulation by PPAR
The above-described data suggest that PPAR
Maintenance of the skin requires a well orchestrated program of keratinocyte proliferation and differentiation during which the cells pass through several phenotypic phases identifiable as distinct layers (Figure
In 1984, an enzyme capable of sulfonating cholesterol was reported to be present in mouse epidermis [
SULT2B1b preferentially sulfonates cholesterol and is the chief SULT2B1 enzyme that is expressed in human keratinocytes [
In addition to its role as structural component, cholesterol 3-sulfate is an important signaling molecule that plays an essential role in keratinocyte differentiation (Figure
In light of the functional role of SULT2B1b in keratinocyte differentiation, corneoctye desquamation and dermal lipid homeostasis, it is reasonable to expect that SULT2B1b should be a target for regulation by lipid-sensing nuclear receptors in the skin. The effects, on SULT2B1b expression, of treating cultured human keratinocytes with chemical activators of PPAR
The UGTs catalyze the transfer of glucuronic acid from a high-energy cofactor, UDP-glucuronic acid, to a xenobiotic or endogenous substrate containing an available nucleophilic center such as a hydroxyl, carboxyl, amino, or thiol group [
Though over 50 individual UGT enzymes have been described [
Like sulfonation, glucuronidation plays a physiological role in the modulation of biologically active endogenous hormones and metabolic intermediates. For example, the activity of UGT1A1 conjugation in the tight control of bilirubin metabolism has established the importance of UGT1A1 genetic polymorphisms in the pathogenesis of toxic hyperbilirubinemias such as the Crigler-Najjar and Gilbert’s syndromes in humans [
It has been more than 40 years since the discovery that clofibrate treatment causes peroxisome proliferation in rat liver [
Clofibrate treatment of rats has also been reported to increase hepatic UGT activity toward
Clofibrate treatment has been consistently reported not to increase UGT activity toward
In another study, treatment of rats with a single dose of the nonfibrate peroxisome proliferator, the fully-fluorinated ten-carbon fatty acid perfluorodecanoic acid, induced hepatic bilirubin UGT activity two-fold, and this induced a state persisted for 3 weeks [
These early findings, in which peroxisome proliferator treatments produced differential effects on various UGT activities, provided a clear indication of the multiplicity of the UGT superfamily. As seen for the cytochromes P450, only certain UGT activities displayed peroxisome proliferator inducibility, predicting the later demonstration that particular UGT genes would be targets of PPAR
UGT1A1 is the major catalyst of bilirubin glucuronidation [
In a study using antipeptide antibodies to examine the effects of drug treatments on rat hepatic microsomal UGT levels, clofibrate treatment was found to increase the immunoreactive protein levels of UGT1A1 and UGT1A5 (termed UGT1B1 and UGT1B5 in that study) along with bilirubin UGT activity [
In a recent study by Senekeo-Effenberger et al. [
In another study, treatment of primary cultured human hepatocytes with activators of PPAR
UGT1A4 was also identified as a significantly upregulated gene in clofibric acid-treated primary cultured human hepatocytes by Affymetrix microarray analysis [
By comparison to the results described by Senekeo-Effenberger et al. [
In human hepatocytes, treatment with a PPAR
In addition to regulation by PPARs, the SULTs and UGTs receive transcriptional input from multiple other nuclear receptors. Here, we do not attempt to be comprehensive but present several findings related to the regulation of hepatic SULT2A expression as an example. Our previous investigations suggested roles for both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR) in the mediation of glucocorticoid-inducible rat hepatic SULT2A expression [
The constitutive androstane receptor (CAR) also partners with RXR and transactivates murine hepatic SULT2A, and possibly human SULT2A1 [
Emerging evidence supports an under-appreciated physiological role for members of the SULT and UGT gene families to serve as modulators of biologically active lipids and to undergo transactivation by lipid-sensing transcription factors such as the PPARs. Particularly in keratinocytes which rely on lipid signaling for the progression of programmed cellular differentiation, the inducible expression of cholesterol sulfotransferase (SULT2B1b) by PPAR activators has been demonstrated. Studies in primary cultured human but not rat hepatocytes clearly demonstrate that PPAR