Vitamin A Supplementation for Different Periods Alters Oxidative Parameters in Lungs of Rats Matheus Augusto de Bittencourt Pasquali, Daniel Pens Gelain, Marcos Roberto de Oliveira, Guilherme Anto ˆnio Behr, Leonardo Lisbo ˆa da Motta, Ricardo Fagundes da Rocha, Fa ´bio Klamt, and Jose ´ Cla ´udio Fonseca Moreira Centro de Estudos em Estresse Oxidativo, Universidade Federal do Rio Grande do Sul, Departamento de Bioquı´mica, Porte Alegre, Rio Grande do Sul, Brazil ABSTRACT Lungs require an adequate supply of vitamin A (retinol) for normal embryonic development, postnatal mat- uration, and maintenance and repair during adult life. However, recent intervention studies revealed that supplementation with retinoids resulted in higher incidence of lung cancer, although the mechanisms underlying this effect are still unknown. Here, we studied the effect of vitamin A supplementation on oxidative stress parameters in lungs of Wistar rats. Vitamin A supplementation at either therapeutic (1,000 and 2,500 IU=kg) or excessive (4,500 and 9,000 IU=kg) doses for 3, 7, or 28 days induced lipid peroxidation, protein carbonylation, and oxidation of protein thiol groups, as well as change in catalase and superoxide dismutase activity. Together, these results suggest that vitamin A supplementation causes significant changes in redox balance, which are frequently associated with severe lung dysfunction. KEY WORDS:  lung  oxidative stress  retinol INTRODUCTION I n the past few years, vitamin A (retinol) and its me- tabolites (retinoids) have been frequently suggested to be an important antioxidant for tissues such as lungs, liver, and heart. 1 Antioxidant activity has been reported for retinol as well as for many pro-vitamin A compounds, including b- and a-carotenes, by a mechanism of free radical scavenging and=or detoxification. 2 It has been demonstrated that reti- noids inhibit cell growth and induce differentiation and ap- optosis in a variety of normal and tumoral cells, thus acting on the prevention of the development of cancer from trans- formed cells. 3,4 In lungs, retinoids are essential for normal morphogenesis during the fetal period, for maturation and remodeling in the perinatal and postnatal periods, and for maintenance of the fully matured lungs. 5 However, clinical trials have demonstrated that the supplementation with ret- inoids may induce deleterious effects. Daily intervention with b-carotene (30 mg) combined with retinyl palmitate (25,000 IU=kg) increased the incidence of lung cancer and colorectal cancer in smokers and asbestos-exposed men. 5–9 Oxidative stress is caused when the production of reactive oxygen species and=or reactive nitrogen species overcomes the cellular antioxidant defense systems. Oxidative stress cause structural changes and=or degradation of nucleic acids, proteins, and lipids. Exogenous antioxidants such as vitamin A contribute to prevent oxidative stress in many systems. 6 However, a growing body of evidence suggests that retinol and other retinoid derivatives may also exert pro-oxidant effects, which might lead to cell oxidative damage, trans- formation, and=or cell death. 10,11 Previously, we showed that retinol induces protein carbonylation and lipid perox- idation and that antioxidant enzyme activities are modulated by retinol 12–16 and all-trans-retinoic acid 12,15 treatments in cultured Sertoli cells. These pro-oxidant effects caused by retinol can lead to impaired cell signaling and induce malignant cell proliferation. 17–19 In addition, vitamin A directly induces overproduction of superoxide anion (O 2  · ) in vitro, resulting in oxidative DNA damage. 20 Increased oxidative stress is a significant part of the path- ogenesis of lung cancer and is observed also in lung diseases such as asthma and chronic obstructive pulmonary disease and parenchymal lung diseases (e.g., idiopathic pulmonary fibrosis and lung granulomatous diseases). 21 Reactive oxygen species=reactive nitrogen species may alter the remodeling of extracellular matrix, apoptosis, and mitochondrial respiration inside cells. 22 In addition, oxidative stress may impair the maintenance of surfactant and the antiprotease screen and the immune modulation in the lung. 22 Because oxidative stress is directly implicated on the pathogenesis of lung cancers and other pulmonary diseases 22,23 and because vitamin A sup- plementation is believed to induce pro-neoplasic effects, de- pending on the doses administered, we decided to investigate Manuscript received 27 November 2008. Revision accepted 10 March 2009. Address correspondence to: Matheus Augusto de Bittencourt Pasquali, Rua Ramiro Barcelos 2600, Anexo Departmento Bioquı´mica, Lab 32, CEP 90035-003, Porto Alegre, RS, Brazil, E-mail: 00124262@ufrgs.br JOURNAL OF MEDICINAL FOOD J Med Food 12 (6) 2009, 1375–1380 # Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition DOI: 10.1089=jmf.2008.0298 1375