Biotransformation of the Mycotoxin Enniatin B1 by CYP P450 3A4 and Potential for Drug-Drug Interactions
Biotransformation of the Mycotoxin Enniatin B1 by CYP P450 3A4 and Potential for Drug-Drug Interactions
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DOI：
10.3390/metabo9080158
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发表时间：
2019-08-01
期刊：
影响因子：
4.1
通讯作者：
Faeste, Christiane K.
中科院分区：
文献类型：
--
作者：
Ivanova, Lada;Denisov, Ilia G.;Faeste, Christiane K.
恩氏菌素（恩斯）是温带气候下常见于谷物中的真菌次生代谢产物。它们的毒性与它们的亲离子性和亲脂性有关。恩斯的生物转化主要通过细胞色素P450 3A（CYP3A）依赖性氧化反应进行。由于CYP 3A4是许多药物和污染物的主要代谢酶，因此与恩斯的可能相互作用是相关的。在本研究中，我们确定了ENNB 1在人肝微粒体（HLM）和含CYP3A4的纳米盘（ND）中的动力学特征和抑制潜力。我们在两种体外系统中均表明ENNB 1主要由CYP3A4代谢，产生至少11种代谢产物。此外，ENNB 1显著降低了典型的CYP3A4底物咪达唑仑（MDZ）的羟基化速率。脱氧雪腐镰刀菌烯醇（DON）是谷物中最常见的真菌毒素，通常与恩斯共存，不被CYP3A4代谢，也不与其活性位点结合。然而，在HLM和ND中，DON影响该生物转化途径的效率。ENNB 1和常用药物孕酮（PGS）和阿托伐他汀（ARVS）内酯的代谢产物形成率显着降低，这表明DON对酶具有一定的亲和力，随后发生构象变化。我们的研究结果强调了药物相互作用研究的重要性，也与天然毒素。
Enniatins (ENNs) are fungal secondary metabolites that frequently occur in grain in temperate climates. Their toxic potency is connected to their ionophoric character and lipophilicity. The biotransformation of ENNs predominantly takes place via cytochrome P450 3A (CYP 3A)-dependent oxidation reactions. Possible interaction with ENNs is relevant since CYP3A4 is the main metabolic enzyme for numerous drugs and contaminants. In the present study, we have determined the kinetic characteristics and inhibitory potential of ENNB1 in human liver microsomes (HLM) and CYP3A4-containing nanodiscs (ND). We showed in both in vitro systems that ENNB1 is mainly metabolised by CYP3A4, producing at least eleven metabolites. Moreover, ENNB1 significantly decreased the hydroxylation rates of the typical CYP3A4-substrate midazolam (MDZ). Deoxynivalenol (DON), which is the most prevalent mycotoxin in grain and usually co-occurrs with the ENNs, was not metabolised by CYP3A4 or binding to its active site. Nevertheless, DON affected the efficiency of this biotransformation pathway both in HLM and ND. The metabolite formation rates of ENNB1 and the frequently used drugs progesterone (PGS) and atorvastatin (ARVS) lactone were noticeably reduced, which indicated a certain affinity of DON to the enzyme with subsequent conformational changes. Our results emphasise the importance of drug-drug interaction studies, also with regard to natural toxins.