Metabolism of 4β-hydroxycholesterol in Humans
Metabolism of 4β-hydroxycholesterol in Humans
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DOI：
10.1074/jbc.m201712200
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发表时间：
2002-08-30
影响因子：
4.8
通讯作者：
Diczfalusy, U
中科院分区：
文献类型：
--
作者：
Bodin, K;Andersson, U;Diczfalusy, U
人体循环中的主要氧化固醇之一是4 β-羟基胆固醇，由胆固醇通过药物代谢酶细胞色素P450 3A 4形成。将氘标记的4 β-羟基胆固醇注射到两名健康志愿者体内，发现表观半衰期分别为64和60 h。我们先前已经确定7 α-、27-和24-羟基胆固醇的半衰期分别为0.5、0.75和14小时。接受某些抗癫痫药物治疗的患者血浆4 β-羟基胆固醇浓度增加了20倍。在这样的患者中，氘标记的4 β-羟基胆固醇的表观半衰期为52小时，表明高血浆浓度是因为合成增加而不是清除受损。在原代人肝细胞中，4 β-羟基胆固醇转化为酸性产物的速率比7 α-羟基胆固醇慢得多，而重组人CYP 7A 1将4 β-羟基胆固醇转化为7 α-羟基化的速率比胆固醇慢得多。CYP 7 B1和CYP 39 A1对4 β-羟基胆固醇无活性。这些结果表明，4 β-羟基胆固醇的高血浆浓度是因为其异常缓慢的消除，可能部分是因为类固醇的7 α-羟基化速率低。研究结果进行了讨论有关的潜在作用的4 β-羟基胆固醇作为配体的核受体LXR。
One of the major oxysterols in the human circulation is 4beta-hydroxycholesterol formed from cholesterol by the drug-metabolizing enzyme cytochrome P450 3A4. Deuterium-labeled 4beta-hydroxycholesterol was injected into two healthy volunteers, and the apparent half-life was found to be 64 and 60 h, respectively. We have determined earlier the half-lives for 7alpha-, 27-, and 24-hydroxycholesterol to be similar to0.5, 0.75, and 14 h, respectively. Patients treated with certain antiepileptic drugs have up to 20-fold increased plasma concentrations of 4beta-hydroxycholesterol. The apparent half-life of deuteriumlabeled 4beta-hydroxycholesterol in such a patient was found to be 52 h, suggesting that the high plasma concentration was because of increased synthesis rather than impaired clearance. 4beta-Hydroxycholesterol was converted into acidic products at a much slower rate than 7alpha-hydroxycholesterol in primary human hepatocytes, and 4beta-hydroxycholesterol was 7alpha-hydroxylated at a slower rate than cholesterol by recombinant human CYP7A1. CYP7B1 and CYP39A1 had no activity toward 4beta-hydroxycholesterol. These results suggest that the high plasma concentration of 4beta-hydroxycholesterol is because of its exceptionally slow elimination, probably in part because of the low rate of 7alpha-hydroxylation of the steroid. The findings are discussed in relation to a potential role of 4beta-hydroxycholesterol as a ligand for the nuclear receptor LXR.