Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice

Alnouti, Yazen; Klaassen, Curtis D.

doi:10.1124/jpet.107.129650

Cited by 83 publications

(82 citation statements)

References 56 publications

(78 reference statements)

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“…However, prototypical agonists for CAR, PPAR, PXR, or FXR did not influence SULT1C2 mRNA levels. These findings are consistent with those of Alnouti and Klaassen (2008) who reported that activators of CAR, PPAR, and PXR had no significant effect on SULT1C2 expression in the livers of male mice, and further suggest that there are some species differences in the regulation of SULT1C2 by nuclear receptors (Rondini et al, 2014).…”

Section: Discussionsupporting

confidence: 82%

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

Rondini

Pant

Kocarek

2015

J Pharmacol Exp Ther

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Cytosolic sulfotransferase 1C2 (SULT1C2) is expressed in the kidney, stomach, and liver of rats; however, the mechanisms regulating expression of this enzyme are not known. We evaluated transcriptional regulation of SULT1C2 by mevalonate (MVA)-derived intermediates in primary cultured rat hepatocytes using several cholesterol synthesis inhibitors. Blocking production of mevalonate with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin (30 mM), reduced SULT1C2 mRNA content by ∼40% whereas the squalene synthase inhibitor squalestatin (SQ1, 0.1 mM), which causes accumulation of nonsterol isoprenoids, increased mRNA content by 4-fold. Treatment with MVA (10 mM) strongly induced SULT1C2 mRNA by 12-fold, and this effect was blocked by inhibiting squalene epoxidase but not by more distal cholesterol inhibitors, indicating the effects of MVA are mediated by postsqualene metabolites. Using rapid amplification of cDNA ends (RACE), we characterized the 59 end of SULT1C2 mRNA and used this information to generate constructs for promoter analysis. SQ1 and MVA increased reporter activity by ∼1.6-and 3-fold, respectively, from a construct beginning 49 base pairs (bp) upstream from the longest 59-RACE product (-3140:-49). Sequence deletions from this construct revealed a hepatocyte nuclear factor 1 (HNF1) element (-2558), and mutation of this element reduced basal (75%) and MVA-induced (30%) reporter activity and attenuated promoter activation following overexpression of HNF1a or 1b. However, the effects of SQ1 were localized to a more proximal promoter region (-281:-49). Collectively, our findings demonstrate that cholesterol biosynthetic intermediates influence SULT1C2 expression in rat primary hepatocytes. Further, HNF1 appears to play an important role in mediating basal and MVA-induced SULT1C2 transcription.

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Section: Discussionsupporting

confidence: 82%

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

Rondini

Pant

Kocarek

2015

J Pharmacol Exp Ther

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“…For example, in germ-free rats, the percentage of BA sulfates was about 10-fold higher in female than male fecal contents ( 23 ). The female-predominant sulfation of LCA is likely due to Sult2a, which is predominantly expressed in female mouse livers but is essentially absent from male mouse livers ( 24 ). Unlike sulfation of LCA, sulfations of CA and CDCA are malepredominant in mouse liver.…”

Section: Sulfation Of Ca and Cdca In Livers Of Mice Fed Basmentioning

confidence: 99%

Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice

Zhang

Klaassen

2010

Journal of Lipid Research

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130

116

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“…Phase II metabolism or conjugation reactions consist of the glutathione S-transferases (Gsts), UDP glucuronosyltransferases (Ugts), and sulfotransferases (Sults) that usually function as detoxification enzymes in the liver (Jancova et al, 2010). The previously noted xenobiotic-and lipid-sensing transcription factors also regulate the expression of other non-P450 phase I enzymes as well as phase II enzymes in the liver (Alnouti and Klaassen, 2008;Knight et al, 2008;Buckley and Klaassen, 2009;Pratt-Hyatt et al, 2013). The GF mouse is an important model that allows mechanistic investigations of the role of intestinal microbiota in host drug metabolism.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

Selwyn

Cheng

Klaassen

et al. 2015

Drug Metabolism and Disposition

112

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Little is known regarding the effect of intestinal microbiota modifiers, such as probiotics and conventionalization with exogenous bacteria, on host hepatic drug metabolism. Therefore, the goal of this study was to determine the effect of these modifiers on the expression of various drug-metabolizing enzymes of the host liver. VSL3 is a probiotic that contains eight live strains of bacteria. Five groups of mice were used: 1) conventional mice (CV), 2) conventional mice treated with VSL3 in drinking water, 3) germ-free (GF) mice, 4) GF mice treated with VSL3, and 5) GF mice exposed to the conventional environment for 2 months. All mice were 3 months old at tissue collection. GF conditions markedly downregulated the cytochrome P450 (P450) 3a gene cluster, but upregulated the Cyp4a cluster, whereas conventionalization normalized their expression to conventional levels [reverse-transcription quantitative polymerase chain reaction (qPCR) and western blot]. Changes in the Cyp3a and 4a gene expression correlated with alterations in the pregnane X receptor and peroxisome proliferator-activated receptor a-DNA binding, respectively (chromatin immunoprecipitation-qPCR). VSL3 increased each bacterial component in the large intestinal content of the CV mice, and increased these bacteria even more in GF mice, likely due to less competition for growth in the GF environment. VSL3 given to conventional mice increased the mRNAs of Cyp4v3, alcohol dehydrogenase 1, and carboxyesterase 2a, but decreased the mRNAs of multiple phase II glutathione-S-transferases. VSL3 given to germ-free mice decreased the mRNAs of UDPglucuronosyltransferases 1a9 and 2a3. In conclusion, conventionalization and VSL3 alter the expression of many drug-metabolizing enzyme s in the liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients.

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Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice

Cited by 83 publications

References 56 publications

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice

Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

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