Differences in metabolism of the marine biotoxin okadaic acid by human and rat cytochrome P450 monooxygenases
Differences in metabolism of the marine biotoxin okadaic acid by human and rat cytochrome P450 monooxygenases
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DOI：
10.1007/s00204-015-1591-9
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发表时间：
2016-08-01
影响因子：
6.1
通讯作者：
Lampen, Alfonso
中科院分区：
文献类型：
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作者：
Kolrep, Franziska;Hessel, Stefanie;Lampen, Alfonso
摄入被海洋生物毒素冈田酸（OA）污染的海鲜可导致腹泻性贝类中毒，并出现恶心、呕吐和腹部绞痛等症状。大鼠和人类肝脏细胞色素P450单加氧酶（CYP）代谢OA。然而，代谢OA的肝细胞毒性主要是不清楚的。本研究的目的是检测在存在大鼠和人重组β-内酰胺酶的情况下，OA暴露于HepG 2细胞中的细胞效应，以调查种属差异。结果应与CYP特异性代谢物模式相关。采用LC-MS/MS技术建立了OA在大鼠和人重组人β-内酰胺酶中孵育后的代谢产物谱。结果表明，OA代谢为含氧代谢物与解毒相关，解毒主要由人CYP 3A 4和CYP 3A 5催化。与人CYP 3A酶相比，大鼠Cyp 3a 1的去铁作用较低，观察到Cyp 3a 2对OA的活化，与OA的总体转化能力较小一致。相比之下，人类和大鼠CYP 1A 2似乎将OA激活为细胞毒性中间体。总之，OA代谢的不同机制可能发生在肝脏中。在低OA剂量下，人类肝脏可能很好地保护免受细胞毒性OA的影响，但对于高贝类消费者来说，不能排除潜在的风险。
The ingestion of seafood contaminated with the marine biotoxin okadaic acid (OA) can lead to diarrhetic shellfish poisoning with symptoms like nausea, vomiting and abdominal cramps. Both rat and the human hepatic cytochrome P450 monooxygenases (CYP) metabolize OA. However, liver cell toxicity of metabolized OA is mainly unclear. The aim of our study was to detect the cellular effects in HepG2 cells exposed to OA in the presence of recombinant CYP enzymes of both rat and human for the investigation of species differences. The results should be set in correlation with a CYP-specific metabolite pattern. Comparative metabolite profiles of OA after incubation in rat and human recombinant CYP enzymes were established by using LC-MS/MS technique. Results demonstrated that metabolism of OA to oxygenated metabolites correlates with detoxification which was mainly catalyzed by human CYP3A4 and CYP3A5. Detoxification by rat Cyp3a1 was lower compared to human CYP3A enzymes and activation of OA by Cyp3a2 was observed, coincident with minor overall conversion capacity of OA. By contrast human and rat CYP1A2 seem to activate OA into cytotoxic intermediates. In conclusion, different mechanisms of OA metabolism may occur in the liver. At low OA doses, the human liver is likely well protected against cytotoxic OA, but for high shellfish consumers a potential risk cannot be excluded.