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

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish
Pages (from-to)30342-30353
Number of pages12
JournalRSC Advances
Volume5
Issue number38
DOIs
Publication statusPublished - 2015

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Resveratrol
Adenosinetriphosphate
Vitamins
Vitamin E
Folic Acid
Cyclophosphamide
Adenosine Triphosphate
Proteins
Acids
Electron Transport Complex IV
Genes
Acrolein
Free radicals
Poisons
Hydrogen peroxide
resveratrol
Brain
Hydrogen Peroxide
Free Radicals
Glutathione

ASJC Scopus subject areas

  • Chemical Engineering(all)
  • Chemistry(all)

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Cylophosphamide elicited intracranial hemorrhage via mitochondrial ROS-hif-1α-ATP depleting pathway - Preventive trials with folic acid, resveratrol and vitamin E. / Hsieh, Chiu Lan; Chen, Kuan Chou; Guan, William W.; Peng, Chiung Chi; Peng, Robert Y.

In: RSC Advances, Vol. 5, No. 38, 2015, p. 30342-30353.

Research output: Contribution to journalArticle

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abstract = "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",
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