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Review of Retinoid Biology: Part 1
Mariana Phillips, MD. (Updated July 2015*)
Retinioid Receptors (Brand names)
Definitions
Retinoid receptors:
Retinoid X receptor a is key partner in heterodimers
with RAR, Vit D, thyroid, and PPAR (peroxisome
proliferator activator receptors
RAR- (87%) > RAR- (13%) > RAR-b (minimally detectable)
RXR (90%) > RXR- > RXR- (not detectable)
Human epidermis is regulated by RXR- and RAR- heterodimers
Natural ligands
RAR- all trans retinoic acid
RXR- 9-cis retinoic acid
First generation retinoids:
Tretinoin (Retin-A most common; many other brand name
formulations available)
Tretinoin (all-trans-retinoic acid) binds to all RAR receptors; a naturally occurring
metabolite of retinol; photo-unstable and may be oxidized by benzoyl peroxide
Isotretinoin (Brands available in the US: Claravis,
Amnesteem, Absorica, Myorisan, Zenatane)
Isotretinoin does not bind to retinoid receptors: metabolized to tretinoin
Oral bioavailability of isotretinoin increased with fatty foods
Retinol (numerous OTC products)
Retinol AKA Vitamin A, precursor of retinoic acid
Retinaldehyde (numerous OTC products)
Retinaldehyde is a precursor of retinoic acid; may be as effective as tretinoin
and better tolerated (per small studies)
Second generation retinoids:
Etretinate (Tegison)
Acitretin (Soriatane, Neotigason)
Third generation retinoids (polyaromatic
compounds, AKA arotinoids):
Bexarotene (Targretin)
Etretinate is lipophilic: deposited and stored in fatty tissue for several years
In the presence of alcohol, acitretin is re-esterfied to etretinate, resulting in
prolonged storage and teratogenicity
Bexarotene is a synthetic retinoid analog that selectively activates only retinoid X
receptors. Associated with central hypothyroidism (decreased TSH, decreased T4)
Tazarotene (Tazorac, Fabior, Avage, Zorac)
Tazarotene is the first of a new generation of receptor-selective retinoids
targeting RAR- and RAR- (results in decreased Tsg1, K6, K16, EGF)
Adapalene (Differin)
Adapalenes primary target is RAR-, light stable, highly lipophilic
Retinoid responsive gene / gene products
Effect
Inhibits homeobox proteins, regulatory
transcription factors
Responsible for body axis formation, patterning, limb formation, and other
crucial processes during development- TERATOGENICITY
Retinoids block UV induction of c-Jun
c-Jun and c-Fos are components of the AP-1 transcription factor
Retinoids repress the activity of transcription
factors AP1 and NF-kappa-
Inhibition of AP-1 results in potent anti-proliferative and anti-inflammatory
properties and decreases matrix metalloproteinase synthesis
Reduced NF-kappa- results in decreased pro-inflammatory cytokines
(TNF-, IL-1, IL-6, and IL-8)
Mariana Phillips, M.D.,
is currently an
assistant professor at
the Virginia
Commonwealth
University
in Richmond, Virginia
Retinoids inhibit ornithine decarboxylase
Rate limiting enzyme in phospholipase C pathway
Phospholipase C polyamines (pro-inflammatory)
Retinoids inhibit toll like receptor-2 (TLR-2)
May be important in treatment of acne
Retinoid effects in CTCL
Increase TH1 cytokines and decrease TH2 cytokines
Increase IL-12 and IFN-gamma (anti-neoplastic cytokines)
Increase cell mediated cytotoxicity and stimulate NK-cell activity
Retinoid effects in photoaging
Thinning of the stratum corneum
Thickening of nucleated epidermis, promotes differentiation, increased
keratohyaline granules, Odland body secretion, increased fillagrin
Increased collagen I fibers in the dermis
Decreased matrix metalloproteinases
Increased papillary dermis elastic fibers
Increased production of hyaluronic acid and fibronectin
Retinoids effects in psoriasis (pustular/erythrodermic/
palmaplantar)
Acitretin and isotretinoin are effective in inducing desquamation but only
moderately effective in clearing psoriatic plaques. Highly effective when combined
with 311-nm UVB or PUVA (called re-PUVA).
References
1. Bolognia J, Jorrizo J, Rapini R, et al. Dermatology. 3rd Ed. 3rd Ed. Elsevier Limited; 2012
2. Freedberg I, Eisen A, Wolff K, et al. Fitzpatricks Dermatology in General Medicine. Sixth Edition. McGraw-Hill; 2003.
3. Wolverton, SE. Comprehensive Dermatologic Drug Therapy. W.B. Saunders Company; 2001.
*Reviewed and updated July 2015 by: Alina Goldenberg, MD, Emily deGolian, MD, and Sharon Jacob, MD.
in
DRirections
esidency
p. 1 Fall 2007
