Cylophosphamide elicited intracranial hemorrhage via mitochondrial ROS-hif-1α-ATP depleting pathway - Preventive trials with folic acid, resveratrol and vitamin E

Chiu Lan Hsieh, Kuan Chou Chen, William W. Guan, Chiung Chi Peng, Robert Y. Peng

研究成果: 雜誌貢獻文章同行評審

1 引文 斯高帕斯(Scopus)

摘要

Hepatic CYP2B metabolizes cyclophosphamide (CP) into acrolein and phosphoramide mustard, which are the ultimate toxic teratogenic compounds. To determine whether folic acid (FA), resveratrol (RV) and vitamin E (vitE) could prevent these adverse effects, we carried out this study with CP at 20-60 nM. CP at 40 nM yielded maximum malformation (58.3 ± 4.2%) with a minimum mortality rate (58.3 ± 4.5%) and severe neural tube defects (NTDs). CP (40 nM) was co-administered with nutraceutics (each at 0.2 and 2.0 μM) applied to day-zero chicken embryo models (CEMs) and the biochemical parameters in brains were examined. CP upregulated (vs. control) hydrogen peroxide (HPO) (1.75/1.05 μmol per μg protein), hif-1α gene (1.5 fold), and HIF-1α protein (1.87 fold). CP downregulated glutathione (3.0/5.2 μmol per μg protein), cytochrome c oxidase (CCO) (10/22 U per mg protein) and ATP production (0.52 ± 0.7/1.23 ± 0.4 pmol per μg protein) (p <0.05). FA and RV at 2.0 μM completely suppressed the levels of HPO to lower than 1.0 μmol per μg protein and hif-1α to 20 U per mg protein, and ATP to >1.2 pmol per mg protein. As a consequence, the intracranial hemorrhage was completely alleviated. Interestingly, vitE at 2.0 μM slightly upregulated the hif-1α gene, and suppressed GSH, CCO, and ATP production, which was suggested to be due to limited permeability through the blood brain barrier and the formation of tocopheryl free radicals. Conclusively, CP tends to elicit intracranial hemorrhaging via the mitochondrial ROS-hif-1α-ATP depletion pathway. For the prevention of such teratogenicity, FA and RV at 2.0 μM are more effective than vitE. This journal is
原文英語
頁(從 - 到)30342-30353
頁數12
期刊RSC Advances
5
發行號38
DOIs
出版狀態已發佈 - 2015

ASJC Scopus subject areas

  • 化學工程 (全部)
  • 化學 (全部)

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