■有意和无意的有机磷农药暴露是一个公共卫生问题。有机硫代磷酸化合物需要细胞色素P450系统对其相应的oxon类似物进行代谢生物活化,以充当乙酰胆碱酯酶的有效抑制剂。已知细胞色素P450和农药之间的相互作用包括抑制主要的异源代谢细胞色素P450酶和在遗传水平上的变化。
■在这项体外研究中,用代谢活性细胞系(HepaRG细胞)研究了杀虫剂对硫磷和对氧磷对人细胞色素P450和相关加氧酶的影响.首先,评估暴露于对硫磷和对氧磷后细胞的活力。两种农药对细胞色素P4503A4的抑制作用,该酶是异源生物代谢中的关键酶,通过确定剂量反应曲线进行检查。92加氧酶相关基因转录水平的变化,包括那些重要的细胞色素P450酶,进行了评估。
■HepaRG细胞暴露于浓度高达100µM的对硫磷和对氧磷导致100%的生存力。暴露24小时后,细胞色素P4503A4酶活性显著抑制,表明50%的有效浓度为1.2µM(对硫磷)和2.1µM(对氧磷)。结果表明,参与对硫磷代谢的细胞色素P450明显上调。
■细胞色素P4503A4酶活性的相关变化和与细胞色素P450相关的基因的显著改变表明农药暴露对许多代谢过程的干扰。这项工作的主要局限性涉及使用单一农药和体外模型作为人肝细胞的替代品。
■这项研究的数据可能与急性,威胁生命的有机磷化合物中毒,特别是联合用药,被受影响的细胞色素P450代谢。
UNASSIGNED: Intentional and unintentional organophosphorus pesticide exposure is a public health concern. Organothiophosphate compounds require metabolic bioactivation by the cytochrome P450 system to their corresponding oxon analogues to act as potent inhibitors of acetylcholinesterase. It is known that interactions between cytochrome P450 and pesticides include the inhibition of major xenobiotic metabolizing cytochrome P450 enzymes and changes on the genetic level.
UNASSIGNED: In this in vitro study, the influence of the pesticides parathion and
paraoxon on human cytochrome P450 and associated oxygenases was investigated with a metabolically competent cell line (HepaRG cells). First, the viability of the cells after exposure to parathion and
paraoxon was evaluated. The inhibitory effect of both pesticides on cytochrome P450 3A4, which is a pivotal enzyme in the metabolism of xenobiotics, was examined by determining the dose-response curve. Changes on the transcription level of 92 oxygenase associated genes, including those for important cytochrome P450 enzymes, were evaluated.
UNASSIGNED: The exposure of HepaRG cells to parathion and
paraoxon at concentrations up to 100 µM resulted in a viability of 100 per cent. After exposure for 24 hours, pronounced inhibition of cytochrome P450 3A4 enzyme activity was shown, indicating 50 per cent effective concentrations of 1.2 µM (parathion) and 2.1 µM (
paraoxon). The results revealed that cytochrome P450 involved in parathion metabolism were significantly upregulated.
UNASSIGNED: Relevant changes of the cytochrome P450 3A4 enzyme activity and significant alteration of genes associated with cytochrome P450 suggest an interference of pesticide exposure with numerous metabolic processes. The major limitations of the work involve the use of a single pesticide and the in vitro model as surrogate to human hepatocytes.
UNASSIGNED: The data of this study might be of relevance after survival of acute, life-threatening intoxications with organophosphorus compounds, particularly for the co-administration of drugs, which are metabolized by the affected cytochrome P450.