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首页> 外文期刊>The FEBS journal >Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc
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Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc

机译：细胞色素P450scc代谢维生素D3的途径和产品

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摘要

Cytochrome P450scc (CYP11A1) can hydroxylate vitamin D3 to produce 20-hydroxyvitamin D3 and other poorly characterized hydroxylated products. The present study aimed to identify all the products of vitamin D3 metabolism by P450scc, as well as the pathways leading to their formation. Besides 20-hydroxyvitamin D3, other major metabolites of vitamin D3 were a dihydroxyvitamin D3 and a trihydroxyvitamin D3 product. The dihydroxyvitamin D3 was clearly identified as 20,23-dihydroxyvitamin D3 by NMR, in contrast to previous reports that postulated hydroxyl groups in positions 20 and 22. NMR of the trihydroxy product identified it as 17 alpha,20,23-trihydroxyvitamin D3. This product could be directly produced by P450scc acting on 20,23-dihydroxyvitamin D3, confirming that hydroxyl groups are present at positions 20 and 23. Three minor products of D3 metabolism by P450scc were identified by MS and by examining their subsequent metabolism by P450scc. These products were 23-hydroxyvitamin D3, 17 alpha-hydroxyvitamin D3 and 17 alpha,20-dihydroxyvitamin D3 and arise from the three P450scc-catalysed hydroxylations occurring in a different order. We conclude that the major pathway of vitamin D3 metabolism by P450scc is: vitamin D3 -> 20-hydroxyvitamin D3 -> 20,23-dihydroxyvitamin D3 -> 17 alpha,20,23-trihydroxyvitamin D3. The major products dissociate from the P450scc active site and accumulate at a concentration well above the P450scc concentration. Our new identification of the major dihydroxyvitamin D3 product as 20,23-dihydroxyvitamin D3, rather than 20,22-dihydroxyvitamin D3, explains why there is no cleavage of the vitamin D3 side chain, unlike the metabolism of cholesterol by P450scc.
机译：细胞色素P450scc（CYP11A1）可以使维生素D3羟基化，生成20-羟基维生素D3和其他表征较差的羟基化产物。本研究旨在确定P450scc代谢维生素D3的所有产物，以及导致其形成的途径。除了20-羟基维生素D3外，其他维生素D3的主要代谢产物是二羟基维生素D3和三羟基维生素D3产品。与以前的报道假定在20位和22位的羟基相反，通过NMR将二羟基维生素D3明确鉴定为20,23-二羟基维生素D3。三羟基产物的NMR将其鉴定为17α，20,23-三羟基维生素D3。该产物可以由作用于20,23-二羟基维生素D3的P450scc直接生产，证实羟基存在于20和23位。MS鉴定了P450scc的D3代谢的三个次要产物，然后通过P450scc检查了它们的新陈代谢。这些产物是23-羟基维生素D3、17α-羟基维生素D3和17α，20-二羟基维生素D3，它们来自三个P450scc催化的羟基化顺序不同。我们得出结论，P450scc代谢维生素D3的主要途径是：维生素D3-> 20-羟基维生素D3-> 20,23-二羟基维生素D3-> 17 alpha，20,23-三羟基维生素D3。主要产物从P450scc活性位点解离，并以远高于P450scc浓度的浓度积累。我们将主要的二羟基维生素D3产品重新鉴定为20,23-二羟基维生素D3，而不是20,22-二羟基维生素D3，这解释了为什么维生素D3的侧链没有被裂解，这与P450scc的胆固醇代谢不同。

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