Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosyl-transferases.
Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosyl-transferases.
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DOI：
10.2174/1389200054633853
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发表时间：
2005-07
影响因子：
2.3
通讯作者：
J. Zhou;J. Zhang;W. Xie
中科院分区：
文献类型：
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作者：
J. Zhou;J. Zhang;W. Xie
UDP-葡萄糖醛酸转移酶（UGT）属于II相药物代谢酶。UGT介导葡萄糖醛酸从UDP葡萄糖醛酸转移到主要疏水的异种和内生化学物质，从而促进其解毒和排泄。UGT的表达和/或活性的缺乏可能导致遗传性和获得性疾病，如Crigler-Najjar综合征和黄疸。UGT基因可分为UGT 1A和UGT 2B两个亚家族，各亚家族和各亚型具有组织特异性分布。这种组织特异性的潜在机制尚未完全了解。越来越多的证据表明，核受体（NR），如雄烷X受体（PXR）、组成型雄烷受体（CAR）、过氧化物酶体增殖物激活受体（PPAR）等，可以调节UGT，这种NR介导的调节可能有助于UGT的组织特异性表达模式。这些调节被认为是受体和UGT亚型特异性的。此外，UGT还受到芳烃受体（AhR）和其他组织特异性转录因子的调节。基于其催化外源性物质和内生性物质的葡萄糖醛酸化的能力，UGT在激素稳态、能量代谢、胆红素清除和外源性物质解毒中发挥重要作用。因此，阐明核受体对UGT的调控对于理解UGT在各种生理和病理生理条件下的功能具有广泛的意义。
UDP-glucuronosyltransferases (UGTs) belong to the Phase II drug metabolizing enzymes. UGTs mediate the transfer of glucuronic acid, from UDP glucuronic acid to predominantly hydrophobic xeno- and endobiotic chemicals, thus facilitating their detoxification and excretion. Deficiency in the expression and/or activity of UGTs may lead to genetic and acquired diseases such as Crigler-Najjar syndrome and jaundice. UGT genes are classified into UGT1A and UGT2B subfamily, and each subfamily and each isoform shows tissue-specific distribution pattern. The underlying mechanisms for this tissue specificity are not fully understood. Emerging evidence have demonstrated that nuclear receptors (NR), such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPAR), can regulate UGTs and this NR-mediated regulation may contribute to the tissue-specific expression pattern of UGTs. The regulations are believed to be both receptor- and UGT isoform-specific. In addition, UGTs are also subject to the regulation by aryl hydrocarbon receptor (AhR) and other tissue-specific transcription factors. Based on their capacity to catalyze the glucuronidation of xenobiotics and endobiotics, UGTs play an important role in hormonal homeostasis, energy metabolism, bilirubin clearance, and xenobiotic detoxification. Therefore, elucidating UGT regulation by nuclear receptors has broader significance in understanding UGT's function in various physiological and patho-physiological conditions.