Quote from SecondLifeGuide on October 6, 2024, 5:27 am

This is the most recent article posted to my website, where I give an introduction on how Retinoids work and their function: https://secondlifeguide.com/2024/10/05/what-does-accutane-actually-do/

What is Accutane?

Retinoids are the class of chemicals related to vitamin A. They play a role in regulating a wide range of biological systems, including vision, cell proliferation/differentiation, bone tissue, and the immune system. “Retinoid” is a general term that encompasses a range of molecules, including retinol, retinoic acid, and retinyl esters, as well as synthetic retinoids. The breadth of retinoids’ effects in the body is perhaps greater than that of any other vitamin. Despite retinoids existing in many forms, most retinoid signalling comes from the primary metabolite all-trans retinoic acid (ATRA). ATRA binds to several types of nuclear receptors, including Retinoic Acid Receptor (RAR), Retinoid X Receptor (RXR), and Peroxisome proliferator-activated receptors (PPARs). [1]

Vitamin A is classified as a dietary vitamin because the body cannot synthesize it on its own. The precursor to vitamin A, beta-carotene, can be obtained from plant sources that 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. [2] These retinyl esters do not have a significant role aside from serving as substrates for conversion into other retinoid products in the body, such as 11-cis-retinal for vision. [3]

Retinol itself does not primarily contribute to the biological roles of vitamin A, as it must first be converted into retinoic acid. [4] It is 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 metabolizing enzymes (P450), which would otherwise break down excessive retinoic acid. This allows for greater accumulation of retinoic acid in the cell nucleus. [5]

Isotretinoin (Accutane) is an isomer of retinoic acid; it occurs naturally in very small doses but primarily exerts its effect through the metabolite all-trans-retinoic acid (ATRA). The advantage of administering isotretinoin rather than simply ATRA is that it has a longer half-life, allowing for less frequent administration. Isotretinoin is distinct from ATRA because it has a cis bond on the 13th carbon.

 

Differentiation vs Proliferation

Almost every cell in the body undergoes a life cycle that can be broken into four phases. The first stage being G1 (gap 1) phase, which is where the cell synthesises proteins and mRNA to prepare for cell division. Next the S (synthesis phase) takes place, where DNA is replicated to ensure the genome can be perfectly copied across to the new cell. Next follows the G2 (gap 2) phase, where chromatin condenses into chromosomes. The chromatin is the long string of DNA, that first must be packaged into tight structures called chromosomes. Finally, once all this preparation has taken place the cell can divide though mitosis, and a new cell is formed.

The new copy of chromosomes are separated into a new nucleus and new cell is a copy of the first. Cells can be taken outside of this cycle of replication into G0, or quiescent phase. This might occur because there simply isn’t sufficient nutrients to support the growth of new cells, or because some cells don’t require regeneration unless there is injury. Most cells in adults exist in the G0 phase, and don’t need proliferation. For example, cells in the liver very rarely divide, but when a section of liver is surgically removed or damaged, the cells rapidly proliferate to repair the damage.

During cell proliferation, tissues growth individual cells grow whilst dividing, and therefor maintain cells of a roughly constant size. If the cells did not also grow as they divide, then the tissue mass would remain constant as it divides into smaller and smaller cells. Cells can also change purpose or function through a process of differentiation. A progenitor or stem cell can become specialised to perform specific tissues or functions. Some cells have a short life span and must be replaced by continual cell proliferation such as blood cells and epithelial cells of the skin or digestive tract.

These cells are not replaced through direct proliferation of the differentiated cells however, instead they proliferate from less differentiated stem cells. Stem cells also divide to produce new stem cells and act as reserve for throughout an entire lifetime. However, some cells can proliferate in an uncontrolled manner and avoid the typical cycle of cell death. These cells are called cancer cells and form tumours that disrupt normal tissue function and can ultimately lead to death.

[Fig 4] Cell Proliferation vs. Differentiation

 

What does Accutane Do?

Retinoic acid is needed to help signal for cells to become differentiated and specialised from progenitor or stem cells. However high levels of retinoic acid can directly inhibit cell growth. This is most relevant to foetal development, where cells are rapidly proliferating and differentiating. The mother needs healthy levels of vitamin A ensure that stem cells differentiate appropriately to form new limbs in a process called morphogenesis. The absence of vitamin A leads to uncontrolled proliferation of epithelial stem cells that fail to differentiate. For this reason, there has been a strong interest in retinoids reducing cancer risk.

The skin is one organ that relies on pools of progenitor stem cells to maintain tissue health and regeneration throughout adulthood, and for this reason it’s particularly reliant on Vitamin A to regulate the process of differentiation. Epidermal stem cells go through a process of differentiation to become specialised into skin cells, known as epithelial cells. In this process the cells change shape and begin producing a protein called Keratin, increasing the strength and resilience of the cell. The cells also change shape to become flattened till they eventually form the outermost layer of dead skin cells called the epidermis, which acts as a protective barrier.

Accutane accelerates the process of skin cell turnover by promoting skin cell differentiation. This can lead to improvements in skin texture, particularly in older individuals, as stem cell proliferation naturally slows down with age, reducing the rate of tissue regeneration. However, increasing differentiation may deplete the pool of progenitor stem cells. While retinoids can enhance skin appearance, they may do so at the expense of the long-term ability of cells to proliferate. This could potentially have unintended consequences for other tissues in the body that rely on stem cell pools for growth and maintenance, such as epithelial cells in the gut or progenitor cells in the brain.

 

Unintended Consequences Of Retinoids

By speeding up the process of differentiation, Accutane in essence exerts an anti-proliferative effect. This is the case not only for skin, but for a variety of other organs and tissues too. This is most strikingly observed in embryos overexposed to vitamin A. If these embryos reach full term, they often suffer from underdeveloped limbs and cleft palates. [13] This explains why Accutane is classified as a teratogen (a substance that disrupts normal foetal development and causes congenital disabilities). It is also the reason for the strict guidelines on birth control for women undergoing Accutane treatment.

However,the anti-proliferative effects of Accutane can also be observed in many adult tissues that rely on pools of stem cells for continual renewal and growth, including the skin, intestines, bone marrow, cornea, hair follicles, and brain (particularly the hippocampus). Retinoids such as Accutane trigger the conversion of these stem cells into specialized cells through differentiation.

In doing so, retinoids maintain a delicate balance between proliferation and differentiation, which is why certain tissues are particularly affected by Accutane treatment. The hippocampus, a region of the brain that relies on stem cells to continue developing new neurons during adulthood, is essential for forming new memories. Accutane significantly inhibits hippocampal neurogenesis, disrupting hippocampal-dependent learning. [14]

Although there is evidence that Accutane may be detrimental to cognitive function, the results are sometimes mixed. For instance, when rats were treated with Accutane prior to a two-stage maze task in which both stages were identical, it was found that Accutane impaired explicit memory during the second stage. [15] However, one month after Accutane exposure ended, explicit memory was recovered. This finding was supported by a study in mice that similarly showed a disruption in learning a radial maze task. [16]

Crandall et al. (2004) demonstrated that after 42 days of treatment with retinoic acid, hippocampal cell proliferation had almost halved. From this, they concluded that the decline in memory was directly related to Accutane’s impact on neurogenesis. Nonetheless, when rats were maintained on a long-term vitamin A-deficient diet, they also suffered from deficits in memory and hippocampal neurogenesis. This suggests that retinoic acid signalling must be delicately balanced, as both excessive and insufficient levels can damage memory formation. [17]