Gene regulation for the senescence marker protein DHEA-sulfotransferase by the xenobiotic-activated nuclear pregnane X receptor (PXR)

Ibtissam Echchgadda, Chung S. Song, Tae Sung Oh, Sung Hwan Cho, Omar J. Rivera, Bandana Chatterjee

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Dehydroepiandrosterone (DHEA)-sulfotransferase (SULT2A1) is a phase II metabolizing/detoxifying enzyme with substrate preference for physiological hydroxysteroids, diverse drugs and other xenobiotics. The first-pass tissues (liver and intestine) express SULT2A1 at high levels. In senescent male rodents, Sult2A1 gene transcription in the liver is markedly enhanced and calorie restriction retards this increase. Age-associated loss of the liver expression of androgen receptor in part explains the up-regulation of Sult2A1 expression at late life, since androgen receptor is a negative regulator of this gene. In line with its role in xenobiotic metabolism, the Sult2A1 gene is induced by the pregnane X receptor (PXR). PXR is a xenosensing nuclear receptor that is activated by endobiotic (natural steroids) and xenobiotic (therapeutic drugs and environmental chemicals) molecules. An inverted-repeat arrangement (IR0) of the consensus half site binding sequence for nuclear receptors mediates the xenobiotic induction of the Sult2A1 promoter. The IR0 element is a specific binding site for PXR and its heterodimer partner retinoid X receptor (RXR-α) and it directs PXR-mediated induction of a heterologous promoter. In contrast to the loss of androgen receptor expression, PXR and RXR-α mRNA expression is invariant during aging. Repression by the androgen receptor and induction by PXR may act coordinately to cause the senescence associated and xenobiotic mediated stimulation of Sult2A1 transcription. Increased Sult2A1 expression appears to be an adaptive response to ensure optimal metabolism of Sult2A1 substrates at old age.

Original languageEnglish (US)
Pages (from-to)733-745
Number of pages13
JournalMechanisms of Ageing and Development
Volume125
Issue number10-11 SPEC. ISS.
DOIs
Publication statusPublished - Oct 1 2004

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Keywords

  • Aging
  • Nuclear receptors
  • PXR
  • Sulfonation
  • Sult2A1
  • Xenobiotic metabolism

ASJC Scopus subject areas

  • Aging
  • Developmental Biology

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