Grilo Nádia M, João Correia M, Miranda Joana P, Cipriano Madalena, Serpa Jacinta, Matilde Marques M, Monteiro Emília C, Antunes Alexandra M M, Diogo Lucília N, Pereira Sofia A
CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Eur J Pharm Sci. 2017 Jul 15;105:47-54. doi: 10.1016/j.ejps.2017.05.010. Epub 2017 May 6.
Efavirenz is an anti-HIV drug that presents relevant short- and long-term central nervous system adverse reactions. Its main metabolite (8-hydroxy-efavirenz) was demonstrated to be a more potent neurotoxin than efavirenz itself. This work was aimed to understand how efavirenz biotransformation to 8-hydroxy-efavirenz is related to its short- and long-term neuro-adverse reactions. To access those mechanisms, the expression and activity of Cyp2b enzymes as well as the thiolomic signature (low molecular weight thiols plus S-thiolated proteins) were longitudinally evaluated in the hepatic and brain tissues of rats exposed to efavirenz during 10 and 36days. Efavirenz and 8-hydroxy-efavirenz plasma concentrations were monitored at the same time points. Cyp2b induction had a delayed onset in liver (p<0.001), translating into increases in Cyp2b activity in liver and 8-hydroxy-efavirenz plasma concentration (p<0.001). Moreover, an increase in S-cysteinyl-glycinylated proteins (p<0.001) and in free low molecular weight thiols was also observed in liver. A distinct scenario was observed in hippocampus, which showed an underexpression of Cyp2b as well as a decrease in S-cysteinylated and S-glutathionylated proteins. Additionally, the observed changes in tissues were associated with a marked increase of S-glutathionylation in plasma. Our data suggest that the time course of efavirenz biotransformation results from different mechanisms for its short- and long-term neurotoxicity. The difference in the redox profile between liver and hippocampus might explain why, despite being mostly metabolized by the liver, this drug is neurotoxic. If translated to clinical practice, this evidence will have important implications in efavirenz short- and long-term neurotoxicity prevention and management.
依非韦伦是一种抗HIV药物，会引发相关的短期和长期中枢神经系统不良反应。其主要代谢产物（8-羟基依非韦伦）被证明是一种比依非韦伦本身更有效的神经毒素。这项研究旨在了解依非韦伦向8-羟基依非韦伦的生物转化如何与其短期和长期神经不良反应相关。为了探究这些机制，在暴露于依非韦伦10天和36天的大鼠的肝脏和脑组织中，纵向评估了Cyp2b酶的表达和活性以及硫醇组学特征（低分子量硫醇加S-硫醇化蛋白）。同时监测依非韦伦和8-羟基依非韦伦的血浆浓度。Cyp2b诱导在肝脏中起效延迟（p<0.001），导致肝脏中Cyp2b活性和8-羟基依非韦伦血浆浓度增加（p<0.001）。此外，在肝脏中还观察到S-半胱氨酰甘氨酸化蛋白增加（p<0.001）和游离低分子量硫醇增加。在海马体中观察到了不同的情况，其显示Cyp2b表达不足以及S-半胱氨酸化和S-谷胱甘肽化蛋白减少。此外，观察到的组织变化与血浆中S-谷胱甘肽化的显著增加有关。我们的数据表明，依非韦伦生物转化的时间进程源于其短期和长期神经毒性的不同机制。肝脏和海马体之间氧化还原特征的差异可能解释了为什么尽管这种药物主要在肝脏中代谢，但它仍具有神经毒性。如果转化为临床实践，这一证据将对依非韦伦短期和长期神经毒性的预防和管理具有重要意义。
