Vitamin A is a hormone.
Hormones function differently than vitamins or minerals. To support hormones, we need to support a handful of nutrients and metabolic processes. An issue with vitamin A is really an issue with sulfite metabolism, ceruloplasmin, and bile function - not the vitamin itself.
Population carries BCMO1 gene variants
Ceruloplasmin increase from retinoic acid
RBP mRNA increase during zinc deficiency
Hormones are dashboard gauges.
Hormones are similar to gauges on the dashboard of our vehicle. The gasoline an engine runs on is like a nutrient, and the temperature gauge reading is like a hormone level. If the hormone level is incorrect, the hormone itself has very little to do with the issue.
The Molybdenum-Sulfite Connection
The molybdenum cofactor (MoCo) serves as the essential prosthetic group for sulfite oxidase. When MoCo fails, sulfite accumulates and depletes cellular glutathione through formation of GSSO3H, a competitive inhibitor of glutathione S-transferases.
The Bile Acid Connection
The Farnesoid X Receptor (FXR) heavily regulates hepatic vitamin A storage. FXR-null mice show over 90% reduction in hepatic retinol and retinyl palmitate levels. Bile acids are critical for vitamin A homeostasis.
Cascading trace mineral disruptions.
Selenium-Glutathione System
Selenium-dependent glutathione peroxidase requires adequate glutathione as its reducing substrate. When glutathione depletes from sulfite accumulation, this system fails even when selenium levels remain normal.
Ceruloplasmin Dependency
Ceruloplasmin demonstrates remarkable vitamin A dependency. Retinoic acid injection increases ceruloplasmin activity up to 4-fold within 4 days through direct transcriptional regulation.
Zinc's Critical Role
Zinc deficiency significantly impairs hepatic synthesis of retinol-binding protein. During zinc deficiency, cells show a 7.5-fold increase in RBP mRNA as compensation, yet actual RBP secretion and vitamin A mobilization remain blocked.
Individual genetics determine thresholds.
BCMO1 Gene Variants
Up to 45% of the population carries BCMO1 variants (rs7501331 and rs12934922) that reduce beta-carotene conversion by up to 69%. These "poor converters" may be predisposed to toxicity from preformed vitamin A.
Sulfite Oxidase Deficiency
Isolated sulfite oxidase deficiency from SUOX mutations presents the clearest example. Patients accumulate toxic sulfite, S-sulfocysteine, and thiosulfate while experiencing decreased cysteine availability.
Clinical Toxicity Patterns
Patients with compromised liver function show toxicity at doses as low as 25,000 IU daily. Water-miscible vitamin A preparations prove more toxic than oil-based forms due to rapid absorption overwhelming compromised detoxification.
Phase II bottlenecks trap vitamin A.
The Elimination Pathway
Phase I hydroxylation by CYP26 enzymes produces 4-OH-retinoic acid and 4-oxo-retinoic acid, followed by Phase II conjugation. UGT2B7 is the only human enzyme capable of glucuronidating retinoids.
The Metabolic Trap
When sulfation pathways fail due to PAPS depletion, the burden shifts to UGT2B7-mediated glucuronidation. But pharmacological retinoid concentrations cause rapid UGT2B7 down-regulation - vitamin A cannot be properly conjugated for elimination.
Intestinal Vulnerability
Intestinal tissues show greater sulfotransferase induction by retinoic acid compared to hepatic tissues. Individuals with intestinal dysfunction may be particularly vulnerable to vitamin A accumulation.
Support the system, not just the hormone.
The dramatic variability in vitamin A tolerance stems from multiple genetic factors interacting with sulfur metabolism status. Understanding these interconnected pathways reveals why single-nutrient supplementation often fails - comprehensive metabolic assessment is needed before vitamin A supplementation.