Mechanisms of gender-specific regulation of mouse sulfotransferases (Sults)

Alnouti, Yazen; Klaassen, Curtis D.

doi:10.3109/00498254.2010.535923

Cited by 49 publications

(59 citation statements)

References 41 publications

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“…Sults are cytosolic enzymes that are important in hormone regulation/metabolism and xenobiotic detoxification. Prior studies demonstrate marked gender differences in Sult mRNA expression (Alnouti and Klaassen, 2011). Because sex hormones are important in genderdivergent Sult levels, we hypothesized that pregnancy might alter their expression.…”

Section: Resultsmentioning

confidence: 99%

“…Messenger RNA was quantified either by branched DNA (bDNA) signal amplification (Buckley and Klaassen, 2007;Petrick and Klaassen, 2007;Cui et al, 2010;Alnouti and Klaassen, 2011) or quantitative real-time PCR (qPCR) depending on the availability and specificity of primers. The mRNA expression of mouse Ugt1a1, 1a5, 1a9, 2a3, 2b1, 2b5, 2b34 and 2b35, Sult1a1, 1d1, 2a1/2 and 3a1, Gsta1, a4, m2 and p1, transcription factors and their target genes including AhR, cytochrome P450 1a1 (Cyp1a1), CAR, Cyp2b10, PPARa, Cyp4a14, PXR, and Cyp3a11 was quantified using the bDNA signal amplification assay (Panomics QuantiGene, High Volume bDNA Signal Amplification Kit 1.0; Affymetrix, Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Phase II enzymes are mainly expressed in the liver, with some isoforms also expressed in the gastrointestinal tract, kidneys, and adipose tissue (Bock, 2010;Alnouti and Klaassen, 2011). The regulation of phase II enzyme expression is complex and involves multiple signaling mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Sex divergent expression of specific Ugt isoforms is largely due to different patterns of growth hormone secretion between male and female mice. Likewise, Sult1a1, 1d1, and 2a1/2 mRNAs exhibit female-predominant expression in liver because of the suppressive effects of androgens and growth hormone secretion in male mice (Alnouti and Klaassen, 2011). Therefore, up-or downregulation of phase II enzymes by fluctuations in sex hormones may be important during periods such as pregnancy (Luquita et al, 2001;Sweeney et al, 2006;Papacleovoulou et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Wen

Donepudi

Thomas

et al. 2012

J Pharmacol Exp Ther

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Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo-and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARa, and PXR and their target genes were downregulated, whereas ERa mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARa, PXR, and ERa signaling pathways may be candidate signaling pathways responsible for these changes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Wen

Donepudi

Thomas

et al. 2012

J Pharmacol Exp Ther

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“…It is unclear why the remaining differences in constitutive expression occur in one gender but not the other. This laboratory has previously investigated gender-divergent regulation of Ugt and Sult enzymes (Buckley and Klaassen, 2009b;Alnouti and Klaassen, 2011). Sult enzymes are critically regulated by the stimulatory effects of estrogens and growth hormone secretion patterns and suppressed by androgens.…”

Section: Transcription Factor-gene Interactionsmentioning

confidence: 99%

Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-Null Mice

Aleksunes

Klaassen²

2012

Drug Metab Dispos

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226

161

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ABSTRACT:The transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor ␣ (PPAR␣), and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate genes encoding drug-metabolizing enzymes and transporters in livers of mice after chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drugmetabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor-null mice. Chemical activators were administered intraperitoneally to mice once daily for 4 days. Livers were collected 24 h after the final dose, and total RNA was isolated for mRNA quantification of cytochromes P450, NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion-transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35, Sult5a1, Gstm3, and Mrp4), CAR (Cyp2b10, Aldh1a1, Aldh1a7, Ugt1a1, Ugt2b34, Sult1e1, Sult3a1, Sult5a1, Papps2, Gstt1, Gsta1, Gsta4, Gstm1-4, and Mrp2-4), PXR (Cyp3a11, Ugt1a1, Ugt1a5, Ugt1a9, Gsta1, Gstm1-m3, Oatp1a4, and Mrp3), PPAR␣ (Cyp4a14, Aldh1a1, mGst3, Gstm4, and Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, Gsta4, Gstm1-m4, mGst3, and Mrp3-4). Taken together, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase I, phase II, and transport genes by activators of transcription factors can have implications in development of pharmaceuticals as well as risk assessment of environmental contaminants.

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Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice

Chen

Paonessa

et al. 2018

Cancer Medicine

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Bladder cancer risk is 3‐4 times higher in men than women, but the reason is poorly understood. In mice, male bladder is also more susceptible than female bladder to 4‐aminobiphenyl (ABP), a major human bladder carcinogen; however, female liver is more susceptible than male liver to ABP. We investigated the role of sulfotransferase (Sult) in gender‐related bladder and liver susceptibility to ABP. Sulfation reactions of aromatic amine bladder carcinogens catalyzed by Sult may generate highly unstable and toxic metabolites. Therefore, liver Sult may decrease bladder exposure to carcinogens by promoting their toxic reactions in the liver. Notably, the expression of several liver Sults is suppressed by androgen in male mice. Here, we show that two Sults are critical for gender‐related bladder susceptibility to ABP in mice. We measured tissue level of N‐(deoxyguanosin‐8‐yl)‐4‐aminobiphenyl (dG‐C8‐ABP), a principal ABP‐DNA adduct, as readout of tissue susceptibility to ABP. We identified Sutl1a1 and to a lesser extent Sult1d1 as Sults that promote dG‐C8‐ABP formation in hepatic cells. In mice, gender gap in bladder susceptibility to ABP was narrowed by knocking out Sult1a1 and was almost totally eliminated by knocking out both Sutl1a1 and Sult1d1. This was accompanied by dramatic decrease in ABP genotoxicity in the liver (>97%). These results show the strong impact of the Sults on bladder and liver susceptibility to a human carcinogen. Because liver expression of both Sult1a1 and Sutl1d1 is suppressed by androgen in male mice, our results suggest that androgen renders bladder more exposed to ABP in male mice by suppressing Sult‐mediated ABP metabolism in liver, which increases bladder delivery of carcinogenic metabolites.

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Mechanisms of gender-specific regulation of mouse sulfotransferases (Sults)

Cited by 49 publications

References 41 publications

Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-Null Mice

Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice

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