Vitamin A Toxicity

The first important tip needed to navigate vitamin A literature is to get a grip on the units used:
1 International Unit = 0.3 micrograms retinol or 0.6 micrograms beta carotene
1 Retinol Equivalent = 1 microgram retinol or 6 micrograms beta carotene or 12 micrograms of other mixed carotenoid provitamin A compounds
If that makes sense to you, then perhaps you are not paying attention. How do you convert RE to IU? When it is all retinol? When it is all carotene? When you don't know the proportions of each? The vitamin A IU discount for beta carotene is based on the observation that real-life efficiency for conversion of beta carotene to vitamin A by mucosal oxygenases is about 50%. The RE discount is based on this and the additional assumption that beta carotene is only absorbed with 33% efficiency relative to vitamin A.

The retinol requirement is between 500 and 1000 micrograms per day for humans (How many IU and RE would that be?) Chronic ingestion of as little as 15,000 micrograms per day by adults and 6,000 micrograms per day by children can be be toxic, and birth defects have been noted in women ingesting 25,000 micrograms per day. Human threashold for birth defects is below 0.4 mg/kg/day, contasts with 5 mg/kg/day for other promates, 10 for rabbits, 75 for rats and 100 for mice. In a recent isotretinoin tragedy Lammer et al. documented 23% malformations and 40-60% mental impairment in non-malformed young.

How much polar bear liver would it take to poison a person if it has 6mg/g retinyl ester?

Functions of Vitamin A

• Vision: Retinal is attached to opsin to form rhodopsin in the retina of the eye that reacts with incoming visible light to trigger an amplifying chain of events that leads to cGMP production and a signal to the nervous system. Poor vision has long been a measure of vitamin A deficiency. In the Far West, during the 1930's and 1940's when vitamin A deficiency of summer range forage was being discovered, a useful bioassay was to run subject calves through a maze of hay bales in a darkened barn. But neither A deficiency nor A toxicity kills and injures via poor eyesight...
• Transcription Factor: Cellular binding proteins complex with vitamin A and bind to DNA to trigger the transcription of key growth factors and other important control compounds. In epithelial cells, this hormone-like action of vitamin A is the most important controller of cell size, shape, number and differentiation. Deficiency leads to the formation of keratinized cells with increased cross-linking and terminal differention.

• Conversion of provitamins to active vitamin A by gut (or liver or corpus luteum) oxidases is controlled by the incoming dose, current vitamin A status and genetics. Most animals can tolerate massive doses of beta carotene without sufferring from hypervitaminosis A. The carotene is not toxic and its conversion is downregulated under the onslaught of the dietary dose. Chronic high doses of carotene can result in visible deposition of orange color in the skin, which can be readily observed in animals with light hair coats (such as humans). If one frequents organic food stores or coop grocery stores long enough, one will eventually observe one of these "orange people".
• Formation and storage of retinyl esters in stellate cells of the liver both withdraws excess retinol from circulation and provides a reserve of vitamin A for future use during periods in which dietary vitamin A might be reduced. Carnivores (such as sharks, polar bears and dogs) have enhanced abilities to sequester retinol in this manner, which permits them to dine on vitamin A-rich prey and still survive.
• Oxidation to retinoic acid leads to a variety of catabolic and excretory pathways. Charged, acidic forms can exit in the urine. Less polar forms exit in the feces.
• Glucouronides are another excretable form.
• Our old friends, the P450's, are major players in the preexcretory oxidation of vitamin A. Drugs which crank up the P450's (alcohol, phenobarbital, etc.) decrease vitamin A status by enhancing oxidation. Unfortunately, some of those polar catabolites are associated with their own special toxicities...

When these gatekeepers fail or are overwhelmed by preformed vitamin A, toxic concentrations lead to overstimulation of growth factors and mitosis with higher cell turnover and death. This results in erythema, excema, alopecia, bone extensions, fractures, bone malformations, hepatotoxicity, hemorages, birth defects and death. Did you notice that dermatitis and bone malformations are symptoms of both Vitamin A deficiency and toxicity?

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