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Why do beta-carotene and other provitamins like alpha-carotene not cause vitamin-A toxicity but rather carotenosis (Orange skin) whereas retinal, retinol, and retinoic acid cause vitamin A toxicity with dosage as low as 4000 IU?

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    $\begingroup$ Retinoic acid is a signalling molecule whereas the provitamins are merely precursors. $\endgroup$ – WYSIWYG Dec 10 '15 at 5:19
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Since, you didn't state whether you were referring to a concentrate or not, i'm assuming the following forms of Vitamin A were obtained via pill or topical suspension - except for the Carotenoid.

α-carotene and β-carotene are (primary) precursors to Vitamin A. Likewise with, Retinal, Retinol but not with Retinoic Acid (irreversibly metabolized/end point) however, i'm assuming that these first generation Retinoids are produced via ex situ (a facility) metabolism and hence, they do not contain the carotenoid component that cause yellowing of the skin due to the absence of lipid soluble orange/yellow pigments (Xanthaemia). Albeit, the color of the aforementioned FG retinoids when in a concentrated solid state are all yellow still due to molecular structure - explained in midsection.

For example:
Retinal: Otherwise known as Retinaldehyde, is ingested via meat (as a single/complete molecule) or produced by ingestion of carotenoid containing food-stuff (e.g. carots). The pigment causing the color are, Carotenes. Carotene is a component of the Carotenoid molecule; α-carotene and β-carotene.
Alternatively, Retinal can be produced from the metabolism of β-cryptoxanthin, a Xanthophyll containing compound. Xanthophyll and Carotene are similar in terms of molecular structure, however, a Xanthophyll molecule contains Hydroxyl groups and hence, Oxygen atoms - Carotenes are hydrocarbons.

On that note, hypervitaminosis A can be caused by an over ingestion of α-carotene and β-carotene sources e.g. Carrots, due to the process of metabolism; over an extended period of time.

Generally;
Retinyl ester <=> Retinol <=> Retinal => Retinoic acid


What causes Xanthemia in this context?

α-carotene and β-carotene, are absorbed via (passive) diffusion within the gastrointestinal tract. From there, they are metabolized (not fully/partially) at the the mucousal layer of the intestine for the substance to be transported into the liver. Next, the metabolite is diffused into the peripheral tissues by the blood plasma. This is were the "issue" is: Excretion. Carotenoids are excreted via bowel movements (gastrointestinal secretions), Urination, through the secretion of sebum and by sweating.

If very high levels of Carotenoids are being ingested, the pigment tends to show itself when a "build up" occurs, in the sweet glands of our dermis and more noticeably, in areas of which there are a large amount of sweat glands e.g. nasolabial folds.

The orange color is defined is due to the classification of what Carotenoids are. All carotenoids are tetraterpenoids: essentially being tetraterpenes that have been modified by chemical transformations such as oxidation or cyclization. Furtherly, tetraterpenoids are made up 40 carbon atoms and contain 8 isoprene molecules. α-carotene and β-carotene, are bicylcic tetraterpenoids. This molecular classification may have an affect on the amount of energy that the molecule can absorb, and more formally, the colour. Albeit, the greatest majority of reasoning in regards to the orange color, is in favor of the long conjugated chain'ed structure of the molecule.

Carotenoids absorb light in the blue-green and violet region and reflect the longer yellow, red, and orange wavelengths; these pigments also dispose excess energy out of the cell.


Conclusion

Retinal and Retinal are preformed retinoids and are not obtained by means of carotenoid metabolism so, they won't contain the the yellow/orange dark pigment that is found within some plant-based food (Carotene).

Retinoic Acid, is a retinoid although it's function is as a cell signalling molecule. The difference between it and the other retinoids is the functional group present of the tail of the carbon-carbon backbone

Theoretically, speaking, and due to retinoids having a shorter/less extended conjugated system with less unsaturated (multiple) bonds in the molecules it will have shifted the absorption to shorter wavelengths (The two carotene precursors have 11 conjugated bonds and the latter retinoids contain 5).

Furtherly, I don't think that the carboxyl group attached to the Retinoic acid molecule could be classed as an Auxochrome although the remainder of the retinoic acids carbon-carbon chain is still the molecules Chromophore - likewise with the other retinoids. For example, this would mean that there is possibility that the retinoic acid molecule will be more inclined to absorb shorter wavelengths and hence, less orange/yellow. This is relevant as, you will often find retinoic acid in topical preparations that are used to treat certain dermatological conditions.

I don't think that there is a 100% correct answer for this question as there is no evidence to prove that it would be true in this particular case.

So, you are susceptible to toxicity at lower levels in regards to retinol, retinal and retinoic acid because, of the fact that they are metabolites/concentrates and you need ingest less in order to get to the same point of toxicity. Carotenoids are "raw" in contrast to the preformed retinoids and require breakdown. Look at the image below to get an idea of how much the molecular mass will have reduced when the carotenoid is metabolized into a useful form of Vitamin A.

Another example would be, you needing to eat more daffodil bulbs to get the required dose of Galantamine hydrobromide (used in Alzheimer's disease treatment) - that's a bit different though, to be fair.

Comparison

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