Characterization of the metabolism of fenretinide by human liver microsomes, cytochrome P450 enzymes and UDP-glucuronosyltransferases.
Characterization of the metabolism of fenretinide by human liver microsomes, cytochrome P450 enzymes and UDP-glucuronosyltransferases.
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DOI：
10.1111/j.1476-5381.2010.01104.x
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发表时间：
2011-02
影响因子：
7.3
通讯作者：
Veal GJ
中科院分区：
文献类型：
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作者：
Illingworth NA;Boddy AV;Daly AK;Veal GJ
芬维A胺（4-HPR）是一种视黄酸类似物，目前用于肿瘤学的临床试验。由于活性代谢物4′-氧代4-HPR的产生以及在患者中获得一致的4-HPR血浆浓度的临床挑战，4-HPR的代谢特别令人关注。在这里，我们评估了参与各种4-HPR代谢途径的酶。使用人肝微粒体（HLM）、过表达单个人细胞色素P450（CYP）的supersomes、尿苷5′-二磷酸葡萄糖醛酸转移酶（UGT）和在大肠杆菌中表达的CYP 2C 8变体表征参与4-HPR代谢的酶。通过高效液相色谱法和液相色谱/质谱分析法分析样品，并确定代谢物形成的动力学参数。还使用CYP和甲基化酶抑制剂进行孵育。发现HLM主要产生4′-氧代4-HPR，另外还有一种极性代谢产物4′-羟基4-HPR（4′-OH 4-HPR），由单个CYP产生。发现CYP 2C 8、3A 4和3A 5代谢4-HPR，代谢产物的形成被CYP 3A 4和CYP 2C 8的抑制剂阻止。在2C 8变体中观察到4′-OH 4-HPR的代谢差异，与 *1相比，CYP 2C 8 *4显示出显著较低的Vmax值。相反，在4′-氧代形成方面，观察到CYP 2C 8 *4的Vmax值显著高于 *1。在4-HPR葡萄糖醛酸化方面，UGT 1A 1、1A 3和1A 6产生4-HPR葡萄糖醛酸代谢产物。参与4-HPR代谢的酶已被表征。发现CYP 2C 8亚型对氧化代谢有显著影响，可能具有临床相关性。
Fenretinide (4-HPR) is a retinoic acid analogue, currently used in clinical trials in oncology. Metabolism of 4-HPR is of particular interest due to production of the active metabolite 4′-oxo 4-HPR and the clinical challenge of obtaining consistent 4-HPR plasma concentrations in patients. Here, we assessed the enzymes involved in various 4-HPR metabolic pathways. Enzymes involved in 4-HPR metabolism were characterized using human liver microsomes (HLM), supersomes over-expressing individual human cytochrome P450s (CYPs), uridine 5′-diphospho-glucoronosyl transferases (UGTs) and CYP2C8 variants expressed in Escherichia coli. Samples were analysed by high-performance liquid chromatography and liquid chromatography/mass spectrometry assays and kinetic parameters for metabolite formation determined. Incubations were also carried out with inhibitors of CYPs and methylation enzymes. HLM were found to predominantly produce 4′-oxo 4-HPR, with an additional polar metabolite, 4′-hydroxy 4-HPR (4′-OH 4-HPR), produced by individual CYPs. CYPs 2C8, 3A4 and 3A5 were found to metabolize 4-HPR, with metabolite formation prevented by inhibitors of CYP3A4 and CYP2C8. Differences in metabolism to 4′-OH 4-HPR were observed with 2C8 variants, CYP2C8*4 exhibited a significantly lower Vmax value compared with *1. Conversely, a significantly higher Vmax value for CYP2C8*4 versus *1 was observed in terms of 4′-oxo formation. In terms of 4-HPR glucuronidation, UGTs 1A1, 1A3 and 1A6 produced the 4-HPR glucuronide metabolite. The enzymes involved in 4-HPR metabolism have been characterized. The CYP2C8 isoform was found to have a significant effect on oxidative metabolism and may be of clinical relevance.
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影响因子：
4.8
作者：
Samokyszyn, VM;Gall, WE;Radominska-Pandya, A
通讯作者：
Radominska-Pandya, A
影响因子：
3.6
作者：
Marill, J;Cresteil, T;Chabot, GG
通讯作者：
Chabot, GG
DOI：
10.1097/00008571-200110000-00006
发表时间：
2001-10-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Dai, D;Zeldin, DC;Goldstein, JA
通讯作者：
Goldstein, JA
影响因子：
5.8
作者：
Marill, J;Capron, CC;Chabot, GG
通讯作者：
Chabot, GG
影响因子：
8.8
作者：
通讯作者：
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