Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Czech Republic.
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Czech Republic.
Toxicol Appl Pharmacol. 2019 Apr 1;368:18-25. doi: 10.1016/j.taap.2019.02.002. Epub 2019 Feb 5.
In spite of remarkable reduction in the number of children born with HIV due to antiretroviral therapy, concerns remain on the short- and long-term effects of antiretroviral drugs at the feto-placental unit. Cardio- and skeletal myopathies have been reported in children exposed to antiretroviral drugs prenatally. These conditions have also been described in perturbed placental transfer of l-carnitine, an essential co-factor in fatty acid oxidation. Due to limited fetal and placental synthesis, carnitine supply is maintained through the placental carnitine uptake from maternal blood by the organic cation/carnitine transporters OCTN1 and OCTN2 (SLC22A4 and SLC22A5, respectively). The aim of our study was to investigate potential inhibition of placental carnitine uptake by a broad range of antiretroviral drugs comprising nucleoside/nucleotide reverse transcriptase inhibitors (lamivudine, zidovudine, abacavir, tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (rilpivirine, efavirenz, etravirine), protease inhibitors (ritonavir, lopinavir, atazanavir, saquinavir, tipranavir), integrase inhibitors (raltegravir, dolutegravir, elvitegravir) and viral entry inhibitor, maraviroc. Studies in choriocarcinoma BeWo cells and human placenta-derived models confirmed predominant expression and function of OCTN2 above OCTN1 in l-carnitine transport. Subsequent screenings in BeWo cells and isolated MVM vesicles revealed seven antiretroviral drugs as inhibitors of the Na-dependent l-carnitine uptake, corresponding to OCTN2. Ritonavir, saquinavir and elvitegravir showed the highest inhibitory potential which was further confirmed for ritonavir and saquinavir in placental fresh villous fragments. Our data indicate possible impairment in placental and fetal supply of l-carnitine with ritonavir and saquinavir, while suggesting retained placental carnitine transport with the other antiretroviral drugs.
尽管抗逆转录病毒疗法使因 HIV 而出生的儿童数量显著减少，但人们仍对胎儿-胎盘单位中抗逆转录病毒药物的短期和长期影响感到担忧。有报道称，产前暴露于抗逆转录病毒药物的儿童会出现心脏和骨骼肌肉疾病。这些情况也与胎盘转运左旋肉碱（脂肪酸氧化的必需辅助因子）受到干扰有关。由于胎儿和胎盘合成有限，肉碱的供应通过胎盘肉碱摄取器有机阳离子/肉碱转运体 OCTN1 和 OCTN2（分别为 SLC22A4 和 SLC22A5）从母体血液中维持。我们的研究旨在调查广泛的抗逆转录病毒药物对胎盘肉碱摄取的潜在抑制作用，这些药物包括核苷/核苷酸逆转录酶抑制剂（拉米夫定、齐多夫定、阿巴卡韦、富马酸替诺福韦二吡呋酯）、非核苷逆转录酶抑制剂（利匹韦林、依非韦伦、依曲韦林）、蛋白酶抑制剂（利托那韦、洛匹那韦、阿扎那韦、沙奎那韦、替拉那韦）、整合酶抑制剂（拉替拉韦、多替拉韦、艾维雷韦）和病毒进入抑制剂马拉维若。绒毛膜癌细胞系 BeWo 细胞和人胎盘衍生模型的研究证实，OCTN2 在肉碱转运中比 OCTN1 表达和功能更为突出。随后在 BeWo 细胞和分离的 MVM 囊泡中的筛选显示，七种抗逆转录病毒药物是 Na 依赖性肉碱摄取的抑制剂，对应于 OCTN2。利托那韦、沙奎那韦和艾维雷韦显示出最高的抑制潜能，在胎盘新鲜绒毛碎片中进一步证实了利托那韦和沙奎那韦的抑制潜能。我们的数据表明，利托那韦和沙奎那韦可能会损害胎盘和胎儿左旋肉碱的供应，而其他抗逆转录病毒药物可能会保留胎盘肉碱的转运。
