Beta-carotene breakdown products may impair mitochondrial functions--potential side effects of high-dose beta-carotene supplementation.

Beta-carotene (BC) and other carotenoids are mainly considered as belonging to the group of micronutrients. As they are contained in fruit and vegetables and thus part of human diet, a regular low-dose intake from natural sources is normally assured. In the last decade high-dose supplementation with synthetic carotenoids has been used successfully in the treatment of diseases believed to be associated with oxidative stress. However, in a few clinical studies harmful effects have been observed as well, e.g., a higher incidence of lung cancer after BC was given in high doses to smokers. Our studies aim at shedding light on the causal mechanisms of the known side effects that we have investigated. Possibilities of preventing them are discussed. Obviously, on certain conditions of high-dose carotenoid supplementation, both the antioxidant and prooxidant reactions may arise. Carotenoid breakdown products (CBP) including very reactive aldehydes and epoxides are formed during oxidative attack in the course of antioxidative action. Carotenoid breakdown products inhibit state 3 respiration of isolated rat liver mitochondria at concentrations between 0.5 and 20 microM. In vivo stimulated neutrophils might represent an important source for the generation of CBP, and the lung might be a critical organ in CBP formation. The inhibition of mitochondrial state 3 respiration by CBP is accompanied by a reduced content of protein sulfhydryl groups, decreasing glutathione levels and redox state, and also elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favour functional deterioration of the adenine nucleotide translocator (ANT). The findings reflect a basic mechanism of the side effects of BC supplementation in circumstances of severe oxidative stress induced by CBP representing a class of lipid oxidation products. We are striving for safe conditions of carotenoid supplementation in order to protect patients in need of this kind of medical treatment from possible side effects, such as unwanted prooxidative reactions.