Cholesterol 25-hydroxylation activity of CYP3A
Cholesterol 25-hydroxylation activity of CYP3A
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DOI：
10.1194/jlr.m014084
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发表时间：
2011-08-01
影响因子：
6.5
通讯作者：
Matsuzaki, Yasushi
中科院分区：
文献类型：
--
作者：
Honda, Akira;Miyazaki, Teruo;Matsuzaki, Yasushi
迄今为止，许多研究都是使用 25-羟基胆固醇进行的，它是脂质代谢的有效调节剂。然而，这种氧甾醇的起源尚未完全阐明。胆固醇25-羟化酶是负责25-羟基胆固醇代谢的酶之一，但该酶在人体中的表达量非常低。这种氧甾醇也由甾醇27-羟化酶(CYP27A1)和胆固醇24-羟化酶(CYP46A1)合成，但它只是这些酶的次要产物。我们现在报道CYP3A合成大量的25-羟基胆固醇并且可能参与脂质代谢的调节。孕烯醇酮-16 α-甲腈对 CYP3A 的诱导导致小鼠肝脏细胞系中 25-羟基胆固醇的积累。此外，用 CYP3A 特异性抑制剂醋竹桃霉素处理细胞可显着降低细胞 25-羟基胆固醇浓度。在过表达人重组 CYP3A4 的细胞中，发现胆固醇 25-羟基化的活性高于胆固醇 4 β-羟基化的活性，胆固醇 4 β-羟基化是 CYP3A4 的已知标记活性。此外，正常人血清中的25-羟基胆固醇浓度与4β-羟基胆固醇水平呈正相关（r = 0.650，P < 0.0001，n = 78），但与27-羟基胆固醇或24S-羟基胆固醇水平没有显着相关。这些结果证明了 CYP3A 对 25-羟基胆固醇产生的重要性。-Honda, A.、T. Miyazaki、T. Ikegami、J. Iwamoto、T. Maeda、T. Hirayama、Y. Saito、T. Teramoto 和 Y. Matsuzaki。 CYP3A 的胆固醇 25-羟基化活性。 J.脂质研究。 2011。52：1509-1516。
To date, many studies have been conducted using 25-hydroxycholesterol, which is a potent regulator of lipid metabolism. However, the origins of this oxysterol have not been entirely elucidated. Cholesterol 25-hydroxylase is one of the enzymes responsible for the metabolism of 25-hydroxycholesterol, but the expression of this enzyme is very low in humans. This oxysterol is also synthesized by sterol 27-hydroxylase (CYP27A1) and cholesterol 24-hydroxylase(CYP46A1), but it is only a minor product of these enzymes. We now report that CYP3A synthesizes a significant amount of 25-hydroxycholesterol and may participate in the regulation of lipid metabolism. Induction of CYP3A by pregnenolone-16 alpha-carbonitrile caused the accumulation of 25-hydroxycholesterol in a cell line derived from mouse liver. Furthermore, treatment of the cells with troleandomycin, a specific inhibitor of CYP3A, significantly reduced cellular 25-hydroxycholesterol concentrations. In cells that overexpressed human recombinant CYP3A4, the activity of cholesterol 25-hydroxylation was found to be higher than that of cholesterol 4 beta-hydroxylation, a known marker activity of CYP3A4. In addition, 25-hydroxycholesterol concentrations in normal human sera correlated positively with the levels of 4 beta-hydroxycholesterol (r = 0.650, P < 0.0001, n = 78), but did not significantly correlate with the levels of 27-hydroxycholesterol or 24S-hydroxycholesterol. These results demonstrate the significance of CYP3A on the production of 25-hydroxycholesterol.-Honda, A., T. Miyazaki, T. Ikegami, J. Iwamoto, T. Maeda, T. Hirayama, Y. Saito, T. Teramoto, and Y. Matsuzaki. Cholesterol 25-hydroxylation activity of CYP3A. J. Lipid Res. 2011. 52: 1509-1516.