CURRENT REVIEW Synthetic retinoids in dermatology nes dermatoses, son emploi est Once in the lumen of the gut Elizabeth H. Heller, MD generalement interdit par des effets vitamin A palmitate is hydrolyzed Norman J. Shiffman, MD, FRCPC toxiques graves. Recemment, la syn- by pancreatic lipase to retinol, these et la mise en marche de deux which is then absorbed into the analogues relativement peu toxiques, gastrointestinal mucosa. Beta-caro- The potential of vitamin A, or reti- les retinoides, ont permis de traiter tene is hydrolyzed in two steps to nol, in the treatment of a variety of des dermatoses resistantes aux trai- retinol. Theoretically, one molecule of skin diseases has long been recog- tements habituels. 11 s'agit de l'iso- d-carotene can produce two molecules nized, but because of serious toxic tretinoine, tres efficace contre I'acne of retinol, but in humans the conver- effects this substance generally could kystique et pustuleuse, et de l'etreti- sion is inefficient, and four times as not be used. The recent development nate, fort utile dans les formes gra- much carotene as retinol is needed and marketing of two relatively non- ves du psoriasis. On obtient des to maintain the eyes' normal capaci- toxic synthetic analogues, which are resultats interessants dans certains ty for adaptation to the dark.' known as retinoids, has made it autres troubles de la keratinisation. In the mucosal cells of the gas- possible to treat some of the diseases La vitamine A et ses derives semblent trointestinal tract retinol is esterified that are resistant to standard forms posseder aussi une action antineopla- to form retinyl esters, which are of therapy. Isotretinoin is very effec- sique qui servira peut4tre un jour a then transported to the liver for tive in cystic and conglobate acne, prevenir et a traiter les epitheliomas. storage via chylomicrons in the while etretinate is especially useful in Dans beaucoup de ces maladies, les blood and lymphatic channels. Reti- the more severe forms of psoriasis. retinoides agissent en favorisant, par nol is released from the liver in Good results have also been obtained des voies encore mal comprises, la association with retinol-binding pro- in other disorders of keratinization. differenciation et la proliffration tein and circulates as a protein- Vitamin A and its derivatives appar- normale des tissus epitheliaux. Leur protein aggregate with prealbumin; ently have an antineoplastic effect as action sur les polyamines intracellu- the aggregate, in turn, binds one well and may come to be used in both laires qui regissent la synthese des molecule of thyroxine. the prevention and the treatment of acides nucleiques et des proteines In the peripheral tissues retinol epithelial cancer. In many of these serait un facteur important. Les reti- undergoes reversible oxidation to diseases the retinoids act by enhanc- noides ont peu d'effets generaux gra- retinal and then irreversible oxida- ing the normal differentiation and ves, sauf qu'ils sont teratogenes; tion to retinoic acid. Although the proliferation of epidermal tissues, comme ils persistent dans l'organis- mechanisms are poorly understood, but the exact mechanisms are not me, il faut s'en garder chez les it appears that retinol, retinal and well understood. Their influence on femmes susceptibles d'etre meres. retinoic acid all contribute in specif- the intracellular polyamines that ic ways to the biologic functions control the synthesis of nucleic acids Vitamin A, or retinol, is a fat-solu- attributed to vitamin A. and proteins may be an important ble vitamin important in reproduc- The only system in which the factor. Although the retinoids have tion, the visual cycle, and the differ- action of vitamin A is understood at few serious systemic effects, they are entiation and maintenance of epithe- a molecular level is the visual cycle. teratogenic, and because they persist lial tissues. An esterified form, vita- Retinol is metabolized to all-trans- in the body their use in women of min A palmitate, is supplied in the retinal and then to the isomer childbearing potential is limited. diet by animal sources, such as fish- 1 1-cis-retinal, which interacts with liver oil, eggs, butter and animal opsin to form the visual pigment Si on connalt depuis longtemps ce liver, and by fortified margarine. rhodopsin.' Hence, retinal is -the que peut donner la vitamine A (ou Vitamin A is also derived from the form of vitamin A important in the retinol) dans le traitement de certai- carotenoid pigments, particularly #- visual cycle, and one of the effects of carotene, which is found in many vitamin A deficiency is night blind- green and yellow vegetables. The ness.2 From the Division of Dermatology, the structures of $-carotene, retinol and Although little is known about the Wellesley Hospital, Toronto retinol's important metabolic deriva- role of vitamin A in the reproductive are Correspondence to: Dr. Elizabeth H. Heller, tives, retinal and retinoic acid (treti- tract, animals deprived of retinol 345 Victoria St., London, Ont. N6A 2C7 noin), are shown in Fig. 1. unable to maintain and deliver a - For prescribing information see page 1220 CAN MED ASSOC J, VOL. 132, MAY 15, 1985 1129 viable fetus, and testicular atrophy first used to treat psoriasis in Eur- have been proposed on the basis of due to loss of spermatids is ob- ope in 1973, has been used in trials experimental observations. served.3 Supplementation with reti- in the United States since 1976 and The cell growth and proliferation nol, but not retinoic acid, reverses is approved for treatment of severe that figure in many skin diseases these abnormalities. nodulocystic acne that has not re- depend in part on the intracellular Finally, vitamin A is important in sponded to standard therapy. Since polyamines that control the synthe- the growth and normal differentia- 1982 it has been marketed by Hoff- sis of nucleic acids and proteins.'0 In tion of epithelial tissues. Experimen- mann-La Roche under the trade both psoriasis"' and the early stages tally, vitamin A deficiency causes name Accutane. The aromatic reti- of cancer'2 the activity of ornithine metaplasia of glandular, ciliated, noid etretinate (Ro 10-9359) was decarboxylase, the rate-limiting en- mucus-secreting epithelium and hy- synthesized in 1972 and has also zyme in polyamine biosynthesis, is perkeratosis of keratinizing epitheli- been the subject of much study. It increased. In psoriasis etretinate um.4,5 In the human skin these was recently released as Tegison by therapy causes the levels of this changes produce a condition known the same manufacturer. enzyme to fall;'3 the retinoids also as phrynoderma, in which there are Besides being important in the block the induction of ornithine de- many minute follicular papules. treatment of disorders of keratiniza- carboxylase by tumour promoters.'4 Retinoic acid, inactive in the visual tion, including acne, the retinoids In the cell, proteins that bind and reproductive systems, can cor- are of great interest to oncologists retinol and retinoic acid carry these rect the abnormalities seen in the because of the possibility that they substances to the nucleus, where epithelial tissues of vitamin-A-defi- can be used to prevent and treat a they have an effect on RNA synthe- cient animals.6 variety of premalignant conditions. sis that is analogous to that of the We will now review the mechanisms steroid hormones.'5"6 This effect The development of retinoids of action, pharmacokinetics, side ef- may help explain how retinoids can fects and clinical applications of induce and maintain terminal differ- Because of the similarity between these two drugs in dermatology. entiation in malignant cell lines.'7 phrynoderma and many other skin Gap junctions are lost during ma- diseases involving abnormal keratin- Mechanisms of action lignant transformation; retinoids ization, it was at first thought that a stimulate their production and the deficiency of vitamin A might be The effects of vitamin A and synthesis of glycoproteins, both of involved in the pathogenesis of the retinoids on the skin are poorly which are important in cell commu- other diseases. Vitamin A was there- understood, but many possibilities nication, adhesion and growth.'8"'9 fore used orally in an attempt to treat diseases such as ichthyosis, Darier's disease (keratosis follicula- ris), psoriasis and even acne.78 The high dosages required, however, were associated with serious toxic effects (increased intracranial pres- p-carotene sure, with headache and irritability, as well as changes in the skin, mucous membranes and skeleton). Retinoic acid has been administered topically, mainly in the treatment of acne, but causes skin irritation; it is Vitamin A also impractical for conditions such (retinol) as Darier's disease in which continu- ous treatment of large areas of the body is required. The toxic effects of orally administered retinoic acid on CHO the central nervous system are simi- lar to those of vitamin A.9 A search for less toxic substitutes Retinal for vitamin A led to the develop- ment of the safer analogues known as retinoids. Retinoids are formed by modification of the vitamin A molecule at any one of its three COOH main components: the cyclic end group, the polar end group and the Retinoic acid polyene side chain (Fig. 2). The first retinoid to be synthesized, in 1955, was 13-cis-retinoic acid, also known as isotretinoin (Ro 4-3780). It was Fig. 1-Structures of vitamin A and related compounds. 1130 CAN MED ASSOC J, VOL. 132, MAY 15, 1985 Physiologic doses of retinoids also etretinate. Both etretinate and Ro of lipids and fibrosis seen in biopsy stimulate killer T-cell production 10-1670 are highly bound to plasma specimens.23 Swelling of the feet is and cell-mediated cytotoxicity, proteins.