Methyleugenol, present in herbs and spices, has demonstrated carcinogenic activity in the liver and, to a lesser extent, in extrahepatic tissues of rats and mice. It forms DNA adducts after hydroxylation and sulphation. As previously reported, hepatic DNA adduct formation by methyleugenol in mice is strongly affected by their sulphotransferase (SULT) 1A status. Now, we analysed the adduct formation in extrahepatic tissues. The time course of the adduct levels was determined in transgenic (tg) mice, expressing human SULT1A1/2, after oral administration of methyleugenol (50 mg per kg body mass). Nearly maximal adduct levels were observed 6 h after treatment. They followed the order: liver > caecum > kidney > colon > stomach > small intestine > lung > spleen. We then selected liver, caecum, kidney and stomach for the main study, in which four mouse lines [wild-type (wt), Sult1a1-knockout (ko), tg, and humanized (ko-tg)] were treated with methyleugenol at varying dose levels. In the liver, caecum and kidney, adduct formation was nearly completely dependent on the expression of SULT1A enzymes. In the liver, human SULT1A1/2 led to higher adduct levels than mouse Sult1a1, and the effects of both enzymes were approximately additive. In the caecum, human SULT1A1/2 and mouse Sult1a1 were nearly equally effective, again with additive effects in tg mice. In the kidney, only human SULT1A1/2 played a role: no adducts were detected in wt and ko mice even at the highest dose tested and the adduct levels were similar in tg and ko-tg mice. In the stomach, adduct formation was unaffected by the SULT1A status. IN CONCLUSION (i) the SULT1A enzymes only affected adduct formation in those tissues in which they are highly expressed (mouse Sult1a1 in the liver and caecum, but not in the kidney and stomach; human SULT1A1/2 in the liver, caecum and kidney, not in the stomach of tg mice and humans), indicating a dominating role of local bioactivation; (ii) the additivity of the effects of both enzymes in the liver and caecum implies that the enzyme level was limiting in the adduct formation; (iii) SULT1A forms dominated the activation of methyleugenol in several tissues, but non-Sult1a1 forms or SULT-independent mechanisms were involved in its adduct formation in the stomach.

中文翻译：

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SULT1A状态-野生型，敲除或人源化-对甲基丁香酚在小鼠肝外组织中形成DNA加合物的影响。

存在于草药和香料中的甲基丁香酚在肝脏和大鼠和小鼠的肝外组织中已显示出致癌活性。它在羟基化和硫酸化后形成DNA加合物。如先前报道的，甲基丁香酚在小鼠中形成肝DNA加合物受到其磺基转移酶（SULT）1A状态的强烈影响。现在，我们分析了肝外组织中加合物的形成。口服甲基丁香酚（每公斤体重50 mg）后，在表达人SULT1A1 / 2的转基因（tg）小鼠中确定加合物水平的时程。治疗后6小时观察到几乎最大的加合物水平。他们遵循的顺序是：肝脏>盲肠>肾脏>结肠>胃>小肠>肺>脾脏。然后，我们选择了肝脏，盲肠，肾脏和胃作为主要研究对象，其中以甲基丁香酚以不同剂量水平处理了四只小鼠品系[野生型（wt），Sult1a1-敲除（ko），tg和人源化（ko-tg）]。在肝脏，盲肠和肾脏中，加合物的形成几乎完全取决于SULT1A酶的表达。在肝脏中，人SULT1A1 / 2的加合物水平高于小鼠Sult1a1，这两种酶的作用大致相同。在盲肠中，人SULT1A1 / 2和小鼠Sult1a1几乎同样有效，在tg小鼠中也具有累加作用。在肾脏中，只有人SULT1A1 / 2起作用：即使在测试的最高剂量下，wt和ko小鼠中也未检测到加合物，而tg和ko-tg小鼠中的加合物水平相似。在胃中，加合物的形成不受SULT1A状态的影响。结论（i）SULT1A酶仅影响其高表达组织中的加合物形成（小鼠Sult1a1在肝和盲肠中，但不在肾脏和胃中；人SULT1A1 / 2在肝，盲肠和肾脏中，不在tg小鼠和人类的胃中），表明局部生物激活起主要作用；（ii）肝脏和盲肠中这两种酶作用的可加性暗示该酶水平限制了加合物的形成；（iii）在多种组织中，SULT1A形式主导了甲基丁香酚的活化，但非Sult1a1形式或SULT依赖性机制参与了其在胃中的加合物形成。不在tg小鼠和人类的胃中），表明局部生物激活起主要作用；（ii）肝脏和盲肠中这两种酶作用的可加性暗示该酶水平限制了加合物的形成；（iii）在多种组织中，SULT1A形式主导了甲基丁香酚的活化，但非Sult1a1形式或SULT依赖性机制参与了其在胃中的加合物形成。不在tg小鼠和人类的胃中），表明局部生物激活起主要作用；（ii）肝脏和盲肠中这两种酶作用的可加性暗示该酶水平限制了加合物的形成；（iii）在多种组织中，SULT1A形式主导了甲基丁香酚的激活，但非Sult1a1形式或SULT依赖性机制参与了其在胃中的加合物形成。