State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850 People's Republic of China.
Mil Med Res. 2015 Jul 2;2:13. doi: 10.1186/s40779-015-0041-6. eCollection 2015.
T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of one kind of principal phase I drug-metabolizing enzymes (cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.
A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC- QqQ MS) after a simple pretreatment.
In the presence of a carboxylesterase inhibitor, only 20 % T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3 % of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.
Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The primary metabolite produced by carboxylesterase is HT-2, and the main metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.
T-2 毒素对人类健康构成了极大威胁，因为它是目前已知的单端孢霉烯族毒素中毒性最高的一种。为了了解 T-2 毒素的体内毒性和转化机制，我们研究了一种主要的 I 相药物代谢酶（细胞色素 P450 [CYP450] 酶）在 T-2 毒素代谢中的作用，这对于内源性物质和外源性物质的代谢至关重要。我们还研究了羧酸酯酶，它在有毒物质的代谢中也起着重要作用。
采用化学抑制法和重组法研究 CYP450 酶对 T-2 毒素的代谢作用，采用化学抑制法研究羧酸酯酶代谢作用。用人肝微粒体孵育样品，经简单预处理后，采用高效液相色谱-三重四极杆质谱法（HPLC-QQQ MS）进行分析。
在存在羧酸酯酶抑制剂的情况下，只有 20%的 T-2 毒素发生代谢。当 CYP 酶抑制剂和羧酸酯酶抑制剂同时存在时，只有 3%的 T-2 毒素发生代谢。CYP450 酶家族对 T-2 毒素代谢的贡献依次为 CYP3A4、CYP2E1、CYP1A2、CYP2B6 或 CYP2D6 或 CYP2C19。
羧酸酯酶和 CYP450 酶在 T-2 毒素代谢中非常重要，其中羧酸酯酶起主要作用，CYP450 酶起次要作用。CYP3A4 是负责 T-2 毒素代谢的 CYP450 酶家族的主要成员。羧酸酯酶产生的主要代谢产物是 HT-2，CYP3A4 产生的主要代谢产物是 3'-OH T-2。不同的代谢产物表现出不同的毒性。我们的研究结果将为 T-2 毒素的毒性机制、安全性评价和健康风险评估提供有价值的数据。
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