By: Hunter Lang
Hunter Lang P.5
13-cis-Retinoic acid (also known as isotretinoin or Accutane) was developed in 1982 by Hoffmann-La Roche. It was discovered because of the indication that vitamin A can inhibit sebum production at toxic dosages, led to Roche’s breakthrough involving retinoic acid. The chemists conducting this research were looking for a drug, but didn’t realize all of its true capabilities until later.
This drug is prescribed to treat severe, or even cystic, acne but it can also help prevent and treat skin, brain and pancreatic cancers. When the drug was first discovered, high dosages were extremely prevalent, but throughout the years the dosages became smaller and smaller because research discovered that the excessive dosage was unnecessary. High-dose treatments are administered between 0.5 mg/kg/day to 2 mg/kg/day, but a normal dose is 0.5 to 1 mg/kg/day based on body weight. This drug is not commonly prescribed with any other drug because the drug is so strong it does not need another drug., although the use of topical lotions and body washes can be prescribed to help with the dryness associated with the drug. The drug is synthesized from vitamin A and derived into the specific form of retinoic acid. The chemical equation for 13-cis-Retinoic acid is C20H28O2 and the picture below shows the structure of the drug. The drug interacts with the body because retinoic acid acts by binding to the retinoic acid receptor, RAR, which is bound to DNA with the retinoid X receptor in regions, called retinoic acid response elements. Binding of the retinoic acid ligand to RAR alters the conformation of the RAR, which affects the binding of other proteins that either induce or repress transcription of a nearby gene. Retinoic acid receptors control transcription of different sets of genes controlling differentiation of a variety of cell types, thus the target genes regulated depend upon the target cells. In some cells, one of the target genes is the gene for the retinoic acid receptor itself (RAR-beta in mammals), which amplifies the response. Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid. In short the drug the drug binds to the RAR and affects the transcription of the gene to cause the gene to be written in a preferred way. The picture to the right shows an RAR-beta and an RAR-beta antibody Physically, the drug causes dryness, increased acne (inside of 2-3 weeks of beginning), irritation, teratogenicity (birth defects),and in some cases, inflammatory bowel disease, stunted growth, and eye changes. The picture to the right shows how dry the skin can become with the use of this drug. Physiologically the use of isotretinoin has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use. A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects. Recent reviews of the