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Differential metabolism of 4-n- and 4-tert-octylphenols in perfused rat liver.

机译：灌流大鼠肝脏中4-n-和4-叔辛基酚的新陈代谢差异

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Octylphenols, widely used in a variety of detergents and plastics, are known to exhibit estrogenicity in vivo. The details of their metabolism are needed to better understand the endocrine disruptions. We have previously shown that alkylphenols, having short alkyl chains, are glucuronidated and readily excreted into the bile from the liver, while 4-n-nonylphenol, having longer alkyl chains, remains as the alkylphenol's glucuronide in the tissue. This study elucidated the dependence of the metabolism on the shape of the alkyl chains by comparing 4-n-octylphenol and 4-tert-octylphenols in a perfused rat liver. Both octylphenols were highly glucuronidated by the liver microsomal fractions. The Vmax value of 4-tert-octylphenol glucuronidation was twice as high as that of 4-n-octylphenol in the liver microsomes. On the other hand, the Km values, being measures of enzymatic activity against these chemicals, were similar. 4-n-Octylphenol and 4-tert-octylphenol were both glucuronidated by a UDP-glucuronosyltransferase isoform, UGT2B1, expressed in the liver. In the liver perfusion, almost all of the 4-n-octylphenol perfused was metabolized directly to the glucuronide, whereas a portion of 4-tert-octylphenol was hydroxylated and then glucuronidated. The glucuronide of 4-n-octylphenol accumulated in the liver tissue in the same manner as 4-n-nonylphenol, but 4-tert-octylphenol and the hydroxylated metabolites were excreted readily into the bile. Only a small amount of 4-n-octylphenol-glucuronide and glucuronides of 4-tert-octylphenol and its hydroxylated metabolites could be excreted into the bile of Eisai hyperbilirubinemic rats (EHBR). These animals are deficient in xenobiotic conjugate transporter, multidrug resistance-associated protein (MRP-2), indicating that the glucuronides of both octylphenols are transported by MRP-2. These results indicate that the differences in metabolism of these octylphenols are due to the shape of their alkyl chains, suggesting that the estrogenic activities of notonly the parent chemicals but also these metabolites must be taken into consideration.
机译：已知广泛用于各种洗涤剂和塑料中的辛基酚在体内具有雌激素作用。为了更好地了解内分泌干扰，需要详细了解其代谢过程。先前我们已经表明，具有短烷基链的烷基酚被葡萄糖醛酸糖苷酸化，并易于从肝脏排泄到胆汁中，而具有更长烷基链的4-正壬基酚作为烷基酚的葡糖醛酸糖保留在组织中。这项研究通过比较灌流大鼠肝脏中的4-正辛基苯酚和4-叔辛基苯酚，阐明了代谢对烷基链形状的依赖性。两种辛基酚都被肝脏微粒体部分高度葡糖醛酸化。肝微粒体中4-叔辛基苯酚葡糖醛酸化作用的Vmax值是4-正辛基苯酚的Vmax值的两倍。另一方面，Km值（针对这些化学物质的酶活性的度量）相似。 4-正辛基苯酚和4-叔辛基苯酚都被在肝脏中表达的UDP-葡萄糖醛糖基转移酶同工型UGT2B1葡萄糖醛酸化。在肝脏灌注中，几乎所有灌注的4-正辛基苯酚都直接代谢为葡萄糖醛酸，而一部分4-叔辛基苯酚则被羟基化，然后被葡萄糖醛酸化。 4-n-辛基苯酚的葡萄糖醛酸以与4-n-壬基苯酚相同的方式积累在肝组织中，但是4-叔辛基苯酚和羟基化代谢物很容易排入胆汁。 Eisai高胆红素血症大鼠（EHBR）的胆汁中只能排泄少量的4-n-辛基苯酚-葡糖醛酸和4-叔辛基苯酚的葡糖醛酸及其羟基化代谢产物。这些动物缺乏异源共轭物转运蛋白，多药耐药相关蛋白（MRP-2），表明两种辛基酚的葡糖醛酸苷都被MRP-2转运。这些结果表明，这些辛基酚的代谢差异是由于其烷基链的形状所致，这表明不仅要考虑母体化学品的雌激素活性，还要考虑这些代谢物的雌激素活性。

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