Retinoid
Encyclopedia
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth.
Retinoids have many important and diverse functions throughout the body including roles in vision
Visual perception
Visual perception is the ability to interpret information and surroundings from the effects of visible light reaching the eye. The resulting perception is also known as eyesight, sight, or vision...
, regulation of cell proliferation and differentiation, growth of bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
tissue, immune function, and activation of tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s.
Research is also being done into their ability to treat skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
s. Currently 9-cis retinoic acid may be used topically to help treat skin lesions from Kaposi's sarcoma
Kaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...
.
Types
There are three generations of retinoids:- First generation retinoids: which include retinolRetinolRetinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
, retinalRetinalRetinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...
, tretinoinTretinoinTretinoin is the acid form of vitamin A and is also known as all-trans retinoic acid or ATRA. It is a drug commonly used to treat acne vulgaris and keratosis pilaris. It is available as a cream or gel...
(retinoic acidRetinoic acidRetinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
, Retin-A), isotretinoinIsotretinoinIsotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
, and alitretinoinAlitretinoinAlitretinoin, or 9-cis-retinoic acid, is an antineoplastic agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration approval for alitretinoin in February 1999.-Kaposi’s sarcoma:...
.
- Second generation retinoids: which include etretinateEtretinateEtretinate is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis...
and its metabolite acitretinAcitretinAcitretin is a second generation retinoid. It is taken orally, and is typically used for psoriasis....
.
- Third generation retinoids: which include tazaroteneTazaroteneTazarotene is a prescription topical retinoid sold as a cream or gel. This medication is approved for treatment of psoriasis, acne, and sun damaged skin...
, bexaroteneBexaroteneBexarotene is an oral antineoplastic agent indicated by the FDA for cutaneous T cell lymphoma. It has been used off-label for lung cancer, breast cancer, and Kaposi's sarcoma.-Mechanism:...
and AdapaleneAdapaleneAdapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne and is also used to treat keratosis pilaris as well as other skin conditions.- History :Adapalene was approved in 1996 by the U.S...
.
Structure
The basic structure of the retinoid molecule consists of a cyclic end group, a polyenePolyene
Polyenes are poly-unsaturated organic compounds that contain one or more sequences of alternating double and single carbon-carbon bonds. These double carbon-carbon bonds interact in a process known as conjugation, which results in an overall lower energy state of the molecule.Organic compounds with...
side chain and a polar end group. The conjugated system
Conjugated system
In chemistry, a conjugated system is a system of connected p-orbitals with delocalized electrons in compounds with alternating single and multiple bonds, which in general may lower the overall energy of the molecule and increase stability. Lone pairs, radicals or carbenium ions may be part of the...
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
Chromophore
A chromophore is the part of a molecule responsible for its color. The color arises when a molecule absorbs certain wavelengths of visible light and transmits or reflects others. The chromophore is a region in the molecule where the energy difference between two different molecular orbitals falls...
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 receptor
Retinoid receptors are nuclear receptors that bind to retinoids. When bound to a retinoid, they act as transcription factors, altering the expression of genes with corresponding response elements.Subtypes include:...
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.
Absorption
The major source of retinoids from the diet are 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 enzymesSeveral 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 specificites. For example, whereas the pancreatic estrase 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
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, skin cancerSkin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
s, disorders of increased cell turnover (e.g. psoriasis), and photoaging
Photoaging
Photoaging or photoageing is a term used for the characteristic changes induced by chronic UVA and UVB exposure. Tretinoin is the best studied retinoid in the treatment of photoaging...
.
Common skin conditions treated by retinoids include acne
Acne vulgaris
Acne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
and psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
.
Isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
is not only considered the only known possible cure of acne in some patients, but was originally a chemotherapy treatment for certain cancers, such as leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
.
Synthesis
Retinoids can be synthesized in a variety of ways. A common procedure to lower retinoid toxicity and improve retinoid activity is glucuronidation. Walker, et al. has proposed a novel synthesis to accomplish glucuronidation.Toxicity
Toxic effects occur with prolonged high intake. The specific toxicity is related to exposure time and the exposure concentration. A medical signMedical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....
of chronic poisoning is the presence of painful tender swellings on the long bones. Anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, skin lesions, hair loss, hepatosplenomegaly
Hepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
, papilloedema, bleeding
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
, general malaise
Malaise
Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...
, pseudotumor cerebri, and death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
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
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...
proguanil
Proguanil
Proguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...
. It is proposed that drugs such as proguanil
Proguanil
Proguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...
act to disrupt retinoid homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
.
Systemic retinoids (isotretinoin, etretinate) are contraindicated during pregnancy as they may cause CNS, cranio-facial, cardiovascular and other defects.