Bodin Karl, Andersson Ulla, Rystedt Eva, Ellis Ewa, Norlin Maria, Pikuleva Irina, Eggertsen Gösta, Björkhem Ingemar, Diczfalusy Ulf
Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden.
J Biol Chem. 2002 Aug 30;277(35):31534-40. doi: 10.1074/jbc.M201712200. Epub 2002 Jun 20.
One of the major oxysterols in the human circulation is 4 beta-hydroxycholesterol formed from cholesterol by the drug-metabolizing enzyme cytochrome P450 3A4. Deuterium-labeled 4 beta-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 7 alpha-, 27-, and 24-hydroxycholesterol to be approximately 0.5, 0.75, and 14 h, respectively. Patients treated with certain antiepileptic drugs have up to 20-fold increased plasma concentrations of 4 beta-hydroxycholesterol. The apparent half-life of deuterium-labeled 4 beta-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. 4 beta-Hydroxycholesterol was converted into acidic products at a much slower rate than 7 alpha-hydroxycholesterol in primary human hepatocytes, and 4 beta-hydroxycholesterol was 7 alpha-hydroxylated at a slower rate than cholesterol by recombinant human CYP7A1. CYP7B1 and CYP39A1 had no activity toward 4 beta-hydroxycholesterol. These results suggest that the high plasma concentration of 4 beta-hydroxycholesterol is because of its exceptionally slow elimination, probably in part because of the low rate of 7 alpha-hydroxylation of the steroid. The findings are discussed in relation to a potential role of 4 beta-hydroxycholesterol as a ligand for the nuclear receptor LXR.
人体循环中的主要氧化甾醇之一是由药物代谢酶细胞色素P450 3A4将胆固醇转化而成的4β-羟基胆固醇。将氘标记的4β-羟基胆固醇注入两名健康志愿者体内，发现其表观半衰期分别为64小时和60小时。我们之前已确定7α-、27-和24-羟基胆固醇的半衰期分别约为0.5小时、0.75小时和14小时。接受某些抗癫痫药物治疗的患者血浆中4β-羟基胆固醇的浓度可升高至20倍。在这样一名患者中，氘标记的4β-羟基胆固醇的表观半衰期为52小时，这表明血浆浓度升高是由于合成增加而非清除受损。在原代人肝细胞中，4β-羟基胆固醇转化为酸性产物的速度比7α-羟基胆固醇慢得多，并且重组人CYP7A1将4β-羟基胆固醇7α-羟基化的速度比胆固醇慢。CYP7B1和CYP39A1对4β-羟基胆固醇无活性。这些结果表明，4β-羟基胆固醇的血浆高浓度是由于其异常缓慢的消除，可能部分原因是该类固醇的7α-羟基化速率较低。结合4β-羟基胆固醇作为核受体LXR配体的潜在作用对这些发现进行了讨论。
