## 3 Vitamin A, Its Vitaminoids and Carotenoids' General Profile and Health Benefits
### Vitamin A-Related Bioactive Compounds: Provitamins (Carotenoids)
#### 4.1.1 Oral Absorption and Metabolism of Vitamin A, Its Vitaminoids, and Carotenoids
Retinol, prior to binding to the CRBP, is similarly metabolized into retinal by retinol dehydrogenases, and then retinal dehydrogenases further oxidize irreversibly retinal into acidic ATRA, the final product of vitamin A oxidation that finally binds to the cellular retinoic acid-binding protein (CRABP). ATRA is not able to be reduced back into retinal and retinol or be stored but can be ultimately isomerized into 9-_cis_-retinoic acid and 13-_cis_-retinoic acid (Figure 5) [3,16,77,87,88,90,91]. Considering the plant-derived carotenoids, \(\beta\)-carotene is absorbed from the intestinal lumen, predominantly through a passive diffusion cascade or by the mediation of the scavenger receptor class B1 (SCARB1) transporter [92] and the cluster of differentiation 36 (CD36) [93]. Almost one-half of carotenoids are reportedly absorbed unaltered, while the rest are metabolized into retinol, regarding the body's retinol levels and the diet's fat content. More specifically, \(\beta\)-carotene, after being absorbed in the intestinal lumen, is transferred in the enterocytes, where either it directly binds to the ChM, surpasses the lymphatic system, and enters the blood flow, or is converted to retinal by \(\beta\)-carotene 15,15\({}^{\prime}\)-oxygenase (\(\beta\)-carotene oxygenase 1 (BOC1)) central cleavage (black arrows), which is then either further oxidized into ATRA by aldehyde dehydrogenase 1 family of enzymes (ALDH1s or RALDHs) or reduced to retinol by different forms of alcohol dehydrogenase (ADH) or retinol dehydrogenases (RDH), a process likely to happen in several GI tract locations. ATRA may be further oxidized into a more polar counterpart, namely 4-oxo-retinoic acid (4-oxo-ATRA), by cytochrome P450 (CYP) 26 family enzymes, which is believed to be transcriptionally inactive, while retinol can be further esterified into retinyl esters by the enzyme lecithin retinol acyltransferase (LRAT) [94,95]. ATRA finally, biochemically, partakes in the retinoic acid receptor (RAR) genetic expression [1,3,16,29,77,87,88,91,96]. When \(\beta\)-carotene intake is high, there is only a small conversion rate, and most of its quantity is stored in the adipose tissue and other fat reserves. At this point, it must be clarified that some retinyl esters are metabolized back into retinol, and the remaining are further transported along with the very-low-density (VLDL) and low-density (LDL) lipoproteins (Figures 6 and 7) [3,87,88,97,98]. Figure 4: The cellular pathway of orally given vitamin A and its transportation to target cells. Apart from the usual cellular pathway depicted in Figure 6, an alternative cleavage procedure occurs with ATRA as the end product, where \(\beta\)-carotene is enzymatically metabolized into \(\beta\)-apo-carotenals (able to ultimately be converted into one molecule of retinaldehyde (purple dashed arrow) and \(\beta\)-ionone by \(\beta\)-carotene 9,10\({}^{\prime}\)-oxygenase (or \(\beta\)-carotene oxygenase 2 (BOC2)), eccentric cleavage (purple arrows)) (Figure 7) [98; 99]. Although the metabolic cascades are similar for \(\beta\)-carotene, \(\alpha\)-carotene, and \(\beta\)-cryptoxanthin, their conversion efficiencies differ due to mainly structural differences, as \(\beta\)-carotene is symmetric and highly efficient (two retinal molecules per molecule), in contrast to \(\alpha\)-carotene and \(\beta\)-cryptoxanthin, which are asymmetric and less efficient (1 retinal molecule per molecule) [98; 99]. Apart from the main retinoids present in all metabolic pathways concluding in the target cells, namely retinol, retinal, and retinyl esters, ATRA, isotretinoin (\"Accutane\"), etreinate, and acitretin are also used in oral therapy [3; 87; 88]. For instance, ATRA has shown great potential towards dermatological conditions like skin cancer, psoriasis, acne, and ichthyosis [100]; isotretinoin is used for treating moderate to severe acne  
Figure 5: Vitamin A’s conversion pathway from retinyl palmitate to retinoic acid. Figure 6: The cellular pathway of orally given carotenoids and their transportation to target cells.