ToxSci Advance Access originally published online on February 23, 2005
Toxicological Sciences 2005 85(1):727-734; doi:10.1093/toxsci/kfi130
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Inhibitory Effects of Vitamin A on TCDD-induced Cytochrome P-450 1A1 Enzyme Activity and Expression
Molecular Biology Center, Shantou University Medical College, Shantou, Guangdong 515041
Received October 31, 2004; accepted February 8, 2005
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an extremely potent environmental contaminant that produces a wide range of adverse biological effects, including the induction of cytochrome P450 1A1(CYP1A1) that may enhance the toxic effects of TCDD. Several studies indicated that concurrent supplementation of vitamin A could reduce the toxicity, and potentially inhibit CYP1A1 activity (measured as ethoxyresorufin-O-deethylase [EROD] activity). In the present study, we investigated the in vivo effects of vitamin A on EROD activities and the expression of CYP1A1 in the liver of TCDD-treated mice. In Experiment I, the mice were given a single oral dose of 40 µg TCDD/kg body weight with or without the continuous administration of 2500 IU vitamin A/kg body weight/day, and were killed on day 1, 3, 7, 14, or 28. In Experiment II, the mice were given daily an oral dose of 0.1 µg TCDD/kg body weight with or without supplement of 2000 IU vitamin A/kg body weight, and were killed on day 14, 28, or 42. In both experiments, TCDD caused liver damage and increase in relative liver weights, augmented the EROD activities and CYP1A1 expression, and increased the aryl hydrocarbon receptor (AhR) mRNA expression, but did not alter the AhR nuclear translocator (ARNT) mRNA expression. CYP1A1 mRNA expression and AhR mRNA expression showed a similar time course. The liver damage in TCDD + vitamin A–treated mice was less severe than that in TCDD-treated mice. EROD activities, CYP1A1 expression, and AhR mRNA expression in vitamin A + TCDD–treated mice were lower than those in TCDD-treated mice, indicating that supplementation of vitamin A might attenuate the liver damage caused by TCDD.
Key Words: vitamin A; 2,3,7,8-tetrachlorodibenzo-p-dioxin; CYP1A1; aryl hydrocarbon receptor; AhR nuclear translocator.
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