Bioactivity of carotenoids – Chasms of knowledge

Carotenoid dietary intake, especially within fruits/vegetables and their plasma levels have been associated in many epidemiological studies with a reduced risk of several chronic diseases, including type-2 diabetes, cardiovascular diseases, several types of cancer, and age-related macular degeneration. However, intervention trials with isolated carotenoids (as supplements) have fallen short of fulfilling the hopes that were placed in these lipophilic pigments, often producing no positive or even adverse effects, such as increased lung cancer rate or total mortality. More recent studies have suggested that certain metabolites, and not necessarily the native compounds may be (the most) biologically active ones, such as certain apocarotenals (originating following enzymatic cleavage) and other more polar compounds, acting as more suitable electrophiles to react with transcription factors such as nuclear factor kappa-B (NF-KB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, it appears that questions of dosing are likewise crucial, as may be interactions of non-provitamin A carotenoids and their derivatives with retinoic acid receptors (RAR) or retinoid X receptors (RXR). Furthermore, our picture on carotenoid metabolism may be incomplete, as our knowledge on e.g. the interaction with the microbiota is virtually nil. In this position article, it is aimed to highlight some of the discrepancies that appear to trouble carotenoid-related research, and point out some of the existing gaps in our knowledge.