β-Carotene cleavage products induce oxidative stress in vitro by impairing mitochondrial respiration

Carotenoids are widely used as important micronutrients in food. Furthermore, carotenoid supplementation has been used in the treatment of diseases associated with oxidative stress. However, in some clinical studies harmful effects have been observed, for example, a higher incidence of lung cancer in individuals exposed to extraordinary oxidative stress. The causal mechanisms are still unclear. Carotenoid cleavage products (CCPs), including highly reactive aldehydes and epoxides, are formed during oxidative attacks in the course of antioxidative action. Here, we tested the hypothesis that CCPs may increase oxidative stress by impairing mitochondrial function. We found that CCPs strongly inhibit state 3 respiration of isolated rat liver mitochondria even at concentrations between 0.5 and 20 muM. This was true for retinal, beta-ionone, and mixtures of cleavage products, which were generated in the presence of hypochlorite to mimic their formation in inflammatory regions. The inhibition of mitochondrial respiration was accompanied by a reduction in protein sulfhydryl content, decreasing glutathione levels and redox state, and elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favor functional deterioration of the adenine nucleotide translocator. The findings may reflect a basic mechanism of increasing the risk of cancer induced by CCPs.