Vitamin A (Retinol, Retinyl Esters and Carotenoids)

Mechanism

🍎 Preformed Shapes (Retinoids)

• Retinol: Primary alcohol used as a serum transport standard.
• Retinal: Active aldehyde directly involved in the visual cycle.
• Retinoic Acid: Acidic isomer that acts as a nuclear transcriptional ligand.

🥕 Precursors (Provitamin Carotenoids)

• β-Carotene: Symmetrical, enzymatically cleaved to release two retinal molecules.
• α-Carotene and β-Cryptoxanthin: Asymmetric monomers with lower biological conversion yield.

Mechanism of cellular action

Vitamin A exerts its biological effects through two independent mechanisms:

1. Biochemical Cycle of Vision (Cellular Tracking of the Rods)

In retinal photoreceptor cells (rods), 11-cis-retinal binds covalently to the protein opsin to form rhodopsin. Upon the incidence of a photon (hν), 11-cis-retinal undergoes instantaneous photochemical isomerization to all-trans-retinal:

This structural change alters the three-dimensional conformation of rhodopsin to metarhodopsin II, activating the G-coupled protein (transducin). Transducin activates a specific phosphodiesterase that hydrolyzes cyclic GMP (cGMP), inducing the closure of cGMP-dependent sodium channels in the outer membrane and causing cellular hyperpolarization. This electrical gradient transmits the visual nerve impulse to the optic nerve.

2. Modulation of Epithelial Gene Expression

Retinoic acid binds to specific nuclear receptors: the Retinoic Acid Receptor (RAR) and the Retinoid X Receptor (RXR). The RAR-RXR heterodimer binds to specific DNA sequences called Retinoic Acid Response Elements (RARE), regulating the synthesis of proteins involved in cellular keratinization, mucin production and immune cell differentiation.

Pharmacokinetics

Pharmacokinetics

• Absorption: Requires micellar lipid digestion in the lumen of the duodenum. Retinyl esters are hydrolyzed to free retinol by pancreatic lipases. It is passively absorbed in the proximal jejunum.
• Transport and Storage: It is packaged in chylomicrons and transported to the liver. In hepatocytes, free retinol is re-esterified and stored mainly in hepatic stellate cells (Ito cells). For its export to target tissues, retinol binds to Retinol Binding Protein (RBP), circulating in plasma in a stable trimolecular complex with transthyretin (prealbumin).
• Metabolism: It is oxidized locally in tissues in an irreversible way: Retinol → Retinal → Retinoic Acid. Its final clearance is biliary and urinary as conjugated water-soluble metabolites.

Security

Risk of Teratogenicity and Systemic Toxicity

Retinoic acid and its synthetic derivatives (such as isotretinoin) are potent teratogens that irreversibly alter the development of the embryonic neural crest, inducing craniofacial, cardiac and central nervous system malformations in the fetus. It is strictly contraindicated in pregnant women or women with active pregnancy potential.

Clinical indications, RAM and dosage

Indicated for the treatment and prevention of Xerophthalmia and night blindness, support in fat malabsorption (cystic fibrosis) and therapeutic adjuvant in acute childhood measles (reduces the mortality rate by mitigating damage to the respiratory and digestive mucous membranes).

Adverse reactions due to acute or chronic hypervitaminosis A are manifested by pseudotumor cerebri (benign intracranial hypertension with severe headache and papilledema), generalized skin peeling, hepatomegaly with portal fibrosis and cortical bone pain with hyperostosis. No dosage adjustment is required in renal failure. In advanced cirrhosis, reduce dose due to impaired RBP transport.