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

Runge-Morris M, Kocarek TA - PPAR Res (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA. m.runge-morris@wayne.edu

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig1: 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.

Mentions: 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 1). The SULT and UGT enzymes represent a highly responsive defense system against the mutagenicity of carcinogenic environmental chemicals and the toxicity of xenobiotics and endogenous metabolic intermediates. Members of the nuclear receptor superfamily are particularly important regulators of UGT and SULT 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.


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

Runge-Morris M, Kocarek TA - PPAR Res (2009)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2724710&req=5

fig1: 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.
Mentions: 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 1). The SULT and UGT enzymes represent a highly responsive defense system against the mutagenicity of carcinogenic environmental chemicals and the toxicity of xenobiotics and endogenous metabolic intermediates. Members of the nuclear receptor superfamily are particularly important regulators of UGT and SULT 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.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA. m.runge-morris@wayne.edu

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.

No MeSH data available.


Related in: MedlinePlus