Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity.
Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity.
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DOI：
10.1371/journal.pone.0009907
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发表时间：
2010-03-26
期刊：
影响因子：
3.7
通讯作者：
Holick MF
中科院分区：
文献类型：
--
作者：
Slominski AT;Janjetovic Z;Fuller BE;Zmijewski MA;Tuckey RC;Nguyen MN;Sweatman T;Li W;Zjawiony J;Miller D;Chen TC;Lozanski G;Holick MF
细胞色素P450 SCC将维生素D3代谢为20-羟基维生素D3（20（OH）D3）和20，23（OH）2D 3，以及1-羟基维生素D3代谢为1α，20-二羟基维生素D3（1，20（OH）2D 3）。它还切割7-脱氢胆固醇的侧链，产生7-脱氢双烯醇酮（7 DHP），其可以转化为20（OH）7 DHP。UVB诱导甾体5，7-二烯转化为β-骨化醇（pD）和光甾醇样化合物（pL）。为了确定这些P450 SCC启动途径的生物学意义，我们测试了它们的5，7-二烯前体和开环甾体产物与1α，25-二羟基维生素D3（1，25（OH）2D 3）相比对白血病细胞分化和增殖的影响。这些开环甾体化合物抑制K562人慢性粒细胞和MEL小鼠白血病细胞的增殖并诱导红细胞分化，其中20（OH）D3和20，23（OH）2D 3的效力与1，25（OH）2D 3相同或略弱于1，25（OH）2D 3，而1，20（OH）2D 3、pD和pL化合物的效力略弱或中等。该化合物还抑制HL-60早幼粒细胞和U937早单核细胞人白血病细胞的增殖并诱导单核细胞分化。其中1，25（OH）_2D_3活性最强，20（OH）_3，20，23（OH）_2D_3和1，20（OH）_2D_3活性较弱，pD和pL活性最弱。由于之前已经证明不含侧链（PD）的开环甾类化合物对全身钙水平没有影响，我们在大鼠中进行了额外的测试，发现20（OH）D3在高达1 µg/kg的浓度下没有钙激活活性，而1，20（OH）2D 3是轻度至中度钙激活，1，25（OH）2D 3具有强钙激活活性。我们确定了新的开环甾类化合物，它们是抗白血病治疗的优秀候选者，20（OH）D3值得特别关注，因为其相对较高的效力和缺乏钙离子活性。
Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1α,20-dihydroxyvitamin D3 (1,20(OH)2D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)2D3 being either equipotent or slightly less potent than 1,25(OH)2D3, while 1,20(OH)2D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)2D3 was the most potent, 20(OH)D3, 20,23(OH)2D3 and 1,20(OH)2D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 µg/kg, whereas, 1,20(OH)2D3 was slightly to moderately calcemic and 1,25(OH)2D3 had strong calcemic activity. We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.
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