The retinoids are a class of

chemical compounds A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

that are

vitamer Vitamins occur in a variety of related forms known as vitamers. A vitamer () of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin. Early r ...

s of

vitamin A Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably ...

or are chemically related to it. Retinoids have found use in medicine where they regulate

epithelial cell Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...

growth. Retinoids have many important functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of

tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

s. Research is also being done into their ability to treat

skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...

s. Currently, alitretinoin (9-''cis''-retinoic acid) may be used topically to help treat skin lesions from Kaposi's sarcoma, and

tretinoin Tretinoin, also known as all-''trans'' retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth f ...

(all-''trans''- retinoic acid) is used to treat

acute promyelocytic leukemia Acute promyelocytic leukemia (APML, APL) is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized ...

Types

There are four generations of retinoids: * First generation include

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xeroph ...

retinal Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use reti ...

( retinoic acid),

isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers (squamous-cell carcinoma), and in th ...

, and alitretinoin * Second generation include

etretinate Etretinate (trade name Tegison) is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis. It is a second-generation retinoid. It was subsequently removed from the Canadian market in 1996 and ...

and its metabolite

acitretin Acitretin (trade names Soriatane and Neotigason) is a second-generation retinoid. It is taken orally, and is typically used for psoriasis. Acitretin is an oral retinoid used in the treatment of severe resistant psoriasis. Because of the potential ...

* Third generation include

adapalene Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions. Studies have found adapalene is as effective as other ...

bexarotene Bexarotene, sold under the brand Targretin, is an antineoplastic (anti-cancer) agent used for the treatment of cutaneous T cell lymphoma (CTCL). It is a third-generation retinoid. It was approved by the U.S. Food and Drug Administration (FDA) i ...

, and

tazarotene Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid. It is primarily used for the treatment of plaque psoriasis and acne. Tazarotene is also used as a therapeutic for photoaged and p ...

* Fourth generation includes

Trifarotene Trifarotene, sold under the brand name Aklief, is a medication for the topical treatment of acne vulgaris. It is a retinoid; more specifically, it is a fourth generation selective retinoic acid receptor (RAR)-γ agonist. Trifarotene was g ...

Structure

The basic structure of the hydrophobic retinoid molecule consists of a cyclic end group, a polyene side chain and a polar end group. The

conjugated system In theoretical chemistry, a conjugated system is a system of connected p-orbitals with delocalized electrons in a molecule, which in general lowers the overall energy of the molecule and increases stability. It is conventionally represented ...

formed by alternating C=C double bonds in the polyene side chain are responsible for the color of retinoids (typically yellow, orange, or red). Hence, many retinoids are

chromophore A chromophore is the part of a molecule responsible for its color. The color that is seen by our eyes is the one not absorbed by the reflecting object within a certain wavelength spectrum of visible light. The chromophore is a region in the mo ...

s. Alternation of side chains and end groups creates the various classes of retinoids. First and second generation retinoids are able to bind with several

retinoid receptor Retinoid receptors are nuclear receptors (a class of proteins) that bind to retinoids. When bound to a retinoid, they act as transcription factors, altering the expression of genes with corresponding response elements. Significant age-related dec ...

s due to the flexibility imparted by their alternating single and double bonds. Third generation retinoids are less flexible than first- and second-generation retinoids and therefore, interact with fewer retinoid receptors. Fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019.

Absorption

The major source of retinoids from the diet are plant pigments such as carotenes and retinyl esters derived from animal sources. Retinyl esters are hydrolyzed in the intestinal lumen to yield free retinol and the corresponding fatty acid (i.e. palmitate or stearate). After hydrolysis, retinol is taken up by the enterocytes. Retinyl ester hydrolysis requires the presence of bile salts that serve to solubilize the retinyl esters in mixed micelles and to activate the hydrolyzing enzymes Several enzymes that are present in the intestinal lumen may be involved in the hydrolysis of dietary retinyl esters. Cholesterol esterase is secreted into the intestinal lumen from the pancreas and has been shown, in vitro, to display retinyl ester hydrolase activity. In addition, a retinyl ester hydrolase that is intrinsic to the brush-border membrane of the small intestine has been characterized in the rat as well as in the human. The different hydrolyzing enzymes are activated by different types of bile salts and have distinct substrate specificities. For example, whereas the pancreatic esterase is selective for short-chain retinyl esters, the brush-border membrane enzyme preferentially hydrolyzes retinyl esters containing a long-chain fatty acid such as palmitate or stearate. Retinol enters the absorptive cells of the small intestine, preferentially in the all-trans-retinol form.

Uses

Common skin conditions treated by retinoids include

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

and

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...

. Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of a number of dermatological conditions such as inflammatory skin disorders,

s, such as bexaroten for mycosis fungoides, disorders of increased cell turnover (e.g. psoriasis), photoaging, and skin wrinkles.

Isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers (squamous-cell carcinoma), and in th ...

was originally a chemotherapy treatment for certain cancers, such as

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

Toxicity

Toxic effects occur with prolonged high intake. The specific toxicity is related to exposure time and the exposure concentration. A

medical sign Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

of chronic poisoning is the presence of painful tender swellings on the long bones.

Anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

, skin lesions,

hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

hepatosplenomegaly Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and his ...

, papilloedema,

bleeding Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...

, general

malaise As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century. The term is often used ...

, pseudotumor cerebri, and

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

may also occur. Chronic overdose also causes an increased lability of biological membranes and of the outer layer of the skin to peel. Recent research has suggested a role for retinoids in cutaneous adverse effects for a variety of drugs including the antimalarial drug

proguanil Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resista ...

. It is proposed that drugs such as

act to disrupt retinoid

homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...

. Systemic retinoids (isotretinoin, etretinate) are contraindicated during pregnancy as they may cause CNS, cranio-facial, cardiovascular and other defects.

References

* '' The Pharmacological Basis of Therapeutics'', 10th Edition, Goodman & Gilman. * ''Clinical Pharmacology'', P.N. Bennett & M.J. Brown.

External links

* {{Authority control *