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Abstract
This study was aimed to investigate whether vitamin A deficiency could alter P-GP expression and function in tissues of rats and whether such effects affected the drug distribution in vivo of vitamin A-deficient rats. We induced vitamin A-deficient rats by giving them a vitamin A-free diet for 12 weeks. Then, Abcb1/P-GP expression was evaluated by qRT-PCR and Western blot. qRT-PCR analysis revealed that Abcb1a mRNA levels were increased in hippocampus and liver. In kidney, it only showed an upward trend. Abcb1b mRNA levels were increased in hippocampus, but decreased in cerebral cortex, liver and kidney. Western blot results were in good accordance with the alterations of Abcb1b mRNA levels. P-GP function was investigated through tissue distribution and body fluid excretion of rhodamine 123 (Rho123), and the results proclaimed that P-GP activities were also in good accordance with P-GP expression in cerebral cortex, liver and kidney. The change of drug distribution was also investigated through the tissue distribution of vincristine, and the results showed a significantly upward trend in all indicated tissues of vitamin A-deficient rats. In conclusion, vitamin A deficiency may alter Abcb1/P-GP expression and function in rat tissues, and the alterations may increase drug activity/toxicity through the increase of tissue accumulation.
Highlights
Vitamin A deficiency is a metabolic disorder caused by lack of vitamin A in vivo
The results clearly demonstrated that vitamin A deficiency altered P-GP expression and function in the indicated tissues, and affected P-GP substrate distributions in vivo
QRT-PCR and Western blot analysis (Figures 1 and 2) showed that P-GP expression was in good accordance with Abcb1 mRNA levels in most of the indicated tissues
Summary
Vitamin A deficiency is a metabolic disorder caused by lack of vitamin A in vivo. It may cause various diseases, such as night blindness, retarded growth, malnutrition and even death.vitamin A metabolic disorder may cause cytochromeP450s (CYP450s) and efflux transporters alterations [1,2,3] and alter drug distribution in tissues, accompanied by affecting the toxicity and activity of drugs.The efflux transporters mainly belong to the ATP-binding cassette (ABC) super-families, and substances involved in their transport include amino acids, proteins, polypeptides, metal ions and drugs. Vitamin A deficiency is a metabolic disorder caused by lack of vitamin A in vivo. It may cause various diseases, such as night blindness, retarded growth, malnutrition and even death. Vitamin A metabolic disorder may cause cytochromeP450s (CYP450s) and efflux transporters alterations [1,2,3] and alter drug distribution in tissues, accompanied by affecting the toxicity and activity of drugs. The efflux transporters mainly belong to the ATP-binding cassette (ABC) super-families, and substances involved in their transport include amino acids, proteins, polypeptides, metal ions and drugs. ABC transporters participated in drug efflux transport, comprising P-glycoprotein (P-GP, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRPs1-6, ABCC1-6). P-GP has abundant structural types of substrates and acts as a drug efflux pump, exporting
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