Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone.
Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone.
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DOI：
10.1007/s00204-016-1808-6
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发表时间：
2017-04
影响因子：
6.1
通讯作者：
Schmeiser HH
中科院分区：
文献类型：
--
作者：
Arlt VM;Meinl W;Florian S;Nagy E;Barta F;Thomann M;Mrizova I;Krais AM;Liu M;Richards M;Mirza A;Kopka K;Phillips DH;Glatt H;Stiborova M;Schmeiser HH
暴露于马兜铃酸（AA）引起马兜铃酸肾病（AAN）和巴尔干半岛的地方性肾病（BEN）。已发现人磺基转移酶1A 1（SULT 1A 1）在马兜铃酸I（AAI）体外代谢活化中的作用的证实结果。我们在用AAI和马兜铃酸II（AAII）处理携带功能性人SULT 1A 1-SULT 1A 2基因簇的转基因小鼠（即hSULT 1A 1/2小鼠）和Sult 1a 1（−/−）小鼠后，评价了人SULT 1A 1在体内AA生物活化中的作用。这两种化合物在完整小鼠和体外胞质孵育中形成特征性DNA加合物。然而，我们没有发现hSULT 1A 1/2和野生型（WT）小鼠之间的AAI-/AAII-DNA加合物水平的差异，在所有分析的组织，包括肾脏和肝脏，尽管强烈增强磺基转移酶活性的hSULT 1A 1/2小鼠的肾脏和肝脏相对于WT，肾脏和肝脏参与AA代谢的主要器官。相反，与WT相比，在用3-硝基苯并蒽酮（3-NBA）处理后，hSULT 1A 1/2小鼠中DNA加合物形成强烈增加，3-NBA是另一种致癌芳香族硝基化合物，已知人SULT 1A 1/2对遗传毒性有贡献。我们发现Sult 1a 1（−/−）和WT小鼠体内AAI-/AII-DNA加合物形成没有差异。使用hSULT 1A 1/2、Sult 1a 1（-/-）和WT小鼠的肾和肝胞质组分，我们研究了体外AAI-DNA加合物的形成，但未能发现人SULT 1A 1/2或小鼠Sult 1a 1对AAI生物活化的贡献。我们的研究结果表明，由人SULT 1A 1催化的磺基缀合在体内AAI和AAII的活化途径中不起作用，但在3-NBA生物活化中是重要的。
Exposure to aristolochic acid (AA) causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Conflicting results have been found for the role of human sulfotransferase 1A1 (SULT1A1) contributing to the metabolic activation of aristolochic acid I (AAI) in vitro. We evaluated the role of human SULT1A1 in AA bioactivation in vivo after treatment of transgenic mice carrying a functional human SULT1A1-SULT1A2 gene cluster (i.e. hSULT1A1/2 mice) and Sult1a1(−/−) mice with AAI and aristolochic acid II (AAII). Both compounds formed characteristic DNA adducts in the intact mouse and in cytosolic incubations in vitro. However, we did not find differences in AAI-/AAII-DNA adduct levels between hSULT1A1/2 and wild-type (WT) mice in all tissues analysed including kidney and liver despite strong enhancement of sulfotransferase activity in both kidney and liver of hSULT1A1/2 mice relative to WT, kidney and liver being major organs involved in AA metabolism. In contrast, DNA adduct formation was strongly increased in hSULT1A1/2 mice compared to WT after treatment with 3-nitrobenzanthrone (3-NBA), another carcinogenic aromatic nitro compound where human SULT1A1/2 is known to contribute to genotoxicity. We found no differences in AAI-/AAII-DNA adduct formation in Sult1a1(−/−) and WT mice in vivo. Using renal and hepatic cytosolic fractions of hSULT1A1/2, Sult1a1(−/−) and WT mice, we investigated AAI-DNA adduct formation in vitro but failed to find a contribution of human SULT1A1/2 or murine Sult1a1 to AAI bioactivation. Our results indicate that sulfo-conjugation catalysed by human SULT1A1 does not play a role in the activation pathways of AAI and AAII in vivo, but is important in 3-NBA bioactivation.