Quote from SecondLifeGuide on April 29, 2024, 11:32 am

This is an article from my website, where I explore some of the lasting adverse effects of Accutane treatment - however it's applicable more generally to hypervitaminosis-A: https://secondlifeguide.com/

INTRODUCTION

Vitamin A plays a key role in a variety of biological processes, from regulating cell growth and differentiation, to the maintenance of eye and skin health. It is classified as a dietary vitamin, as the body cannot synthesise it by itself. The precursor to vitamin A, beta-carotene, can be obtained from plant sources which possess orange and red colours, such as carrots. Additionally, retinyl esters can be obtained from animal sources such as beef liver, which is the storage form of Vitamin A that accumulates in the liver and adipose fat. [1]

These retinyl esters don’t have a significant role aside from being a substrate to convert into other Retinals and Retinol products in the body, such as 11-cis-retinal for vision. [2] Retinol itself also doesn’t primarily contribute to the biological roles of vitamin A, as it must be further converted to retinoic acid. [3] It’s believed that Accutane also serves as a substrate for conversion into Retinoic Acid within the cell. The advantage of applying Isotretinoin (Accutane) rather than Retinoic Acid is that it bypasses the body’s metabolising enzymes (P450) that would otherwise breakdown excessive Retinoic Acid. This leads to even greater accumulation of Retinoic Acid in the cell nucleus. [4]

 

RETINOIC ACID FEEDBACK LOOP

Whilst Retinol is evidently necessary for healthy functioning of tissues throughout the body, excessive Retinol can result in spectrum of potentially serious pathologies. Hypervitaminosis A can lead to damage in the same tissues which healthy Retinol levels effectively regulate, such as skin, hair, eyes, the brain and more. Toxic levels of Vitamin A are also teratogenic, meaning they result in congenital disabilities in the developing foetus. [5] In order to avoid some of the disastrous effects of hypervitaminosis A, the body carefully regulates the enzymes that synthesise Retinoic Acid through a negative feedback mechanism. These enzymes are Aldehyde Dehydrogenases (ALDH) and Retinaldehyde Dehydrogenases (RALDH). [6][7]

Unfortunately, these enzymes also share activity in other key processes throughout the body aside from Retinoic Acid synthesis. ALDH is one such enzyme that is subject to repression by excessive Retinoic Acid. [8] However ALDH is also vital for detoxification, among other things, and repression of ALDH can have it’s own nasty consequences for neurological health. ALDH function is particularly relevant in the progression of Parkinson’s disease, where it serves to breakdown the nasty metabolites of Dopamine such as DOPAL. Mutations that limit ALDH activity can result in an acceleration in the neurotoxic processes that contribute to Parkinson’s pathogenesis, potentially pointing to some of the neurological effects of Accutane treatment. [9] By suppressing these detoxifying enzymes, All-Trans-Retinoic-Acid can also improve the efficacy of Chemo drugs in fighting cancer, by enhancing its cytotoxic effects. [10]

 

RETINYL ESTERS CONTRIBUTE TO FEEDBACK

After exposure to excessive Retinoids, it may seem logical that there would be a consequent elevation in Retinyl Esters stored in fatty tissues. Conversely, when the enzyme that stores Retinol as Retinyl Esters (LRAT) is overexpressed, the body can evade some of the consequences of high Retinol supplementation. [11] Indeed, the primary metabolite of Accutane ATRA (All-Trans-Retinoic-Acid) induces this enzyme to store Retinol into Retinyl Esters in adipose tissue. [12][13] Together with the repression of RALDH/ALDH enzymes, and LRAT elevation, the body attempts to achieve some homeostasis. If this constitutes a significant mechanism in humans, it’s reasonable to suggest that dietary Retinols consumed during Accutane treatment would result in elevated RE in adipose tissue. However, the metabolite of Accutane (All-Trans-Retinoic Acid) cannot itself be directly stored in adipose tissue. [1]

The enzyme that converts the stored Retinyl Esters into useable Retinol in circulation are the Retinyl Ester Hydrolases (REHs). A study in mice found that knocking out the lipase HSL (which has REH activity) resulted in an accumulation of Retinyl Esters in adipose tissue. Interestingly these also show a significant reduction in expression for other key enzymes in Retinoic Acid synthesis, such as ALDH and RALDH1. [14] Additionally, PPAR-gamma was also downregulated, an effect also observed in patients treated with Accutane. [15] Therefore the presence Retinyl Esters represents another indirect pathway by which excessive Retinoic Acid signalling homeostatic processes to limit further Retinoic Acid synthesis.  It might be reasonable to question how long someone can go without Vitamin A given adequate storage of Retinyl Esters. As it turns out, a person can go months with a Vitamin A-deficient diet, surviving off the hepatic and adipose stores. [16]

 

CONCLUSION

In conclusion, whilst the metabolite of Accutane (All-Trans-Retinoic Acid) doesn’t itself get stored in adipose tissue, it could increase liver stores of Retinyl Esters from dietary stores. This is because Retinoic Acid increases LRAT activity, which is the enzyme that converts Retinol to Retinyl esters. Furthermore, elevated Retinyl Ester stores could contribute to other homeostatic processes, such as reducing the expression of key Retinoic Acid synthesising enzymes such as ALDH/RALDH. Decreased ALDH/RALDH and lower PPAR-gamma expression are all established to also be features of Accutane treatment. However, it’s hard to say how significant this effect is when compared to the direct repressive effect of ATRA on these enzymes (such as through post-translational modifications).