Assessment of Etiologic Agents in Acne Pathogenesis

Craig N. Burkhart, MSBS, MD, Lorie Gottwald, MD

Disclosures
In This Article

Retinoids

Retinoids, like glucocorticoids and thyroid hormone, bind to cytoplasmic receptors inducing signals, which in the presence of a ligand, are transmitted to the nucleus. At this location, these response elements bind to specific DNA sequence motifs, thereby affecting transcription. Two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are present in skin. Sebocyte activity and differentiation in vitro depends on vitamin A and synthetic retinoids. Accordingly, sebocytes in vitro express copies of several retinoid factors such as RAR and RXR , whose equilibrium interaction with coactivator and corepressor proteins is altered by binding to retinoids, thus altering transcription of several proteins. Retinoids down-regulate lipid synthesis, decrease late-stage sebocyte differentiation, and inhibit sebocyte proliferation.[7] Thus far, the most potent retinoid in inhibiting proliferation and differentiation is isotretinoin.

Retinoid receptors are expressed in a site-specific manner in the skin. RARs have inverse agonists that repress basal transcription, neutral antagonists that do not change transcription but block transcriptional activation by agonists or repression by inverse agonists, and agonists. In keratinocytes both RAR agonists and inverse agonists regulate markers of abnormal differentiation and inflammation.

Retinoic acid also affects the infundibulum. Isotretinoin, adapalene, tazarotene, and other retinoids (also anti-inflammatory) are comedolytic and anticomedogenic. One µmol 13-cis-retinoic acid decreases the rate of cell division in the infundibulum in vitro, which is possibly its major therapeutic effect.[8] Furthermore, infundibular keratinocytes undergo parakeratosis, instead of the normal differentiation, when exposed to 1 µmol 13-cis retinoic acid.[3]

Isotretinoin also interferes with neutrophilic granulocyte and monocyte function. Migration, phagocytosis, superoxide generation, myeloperoxidase-dependent killing function, and antioxidant effects are disrupted by isotretinoin. Isotretinoin also increases hydroxyl radical formation by zymosan stimulated neutrophiles. Isotretinoin does not bind cellular retinoic acid binding protein-II or nuclear receptors. Isotretinoin/retinol combinations have comparable antiproliferative effects on sebocytes to isotretinoin alone. Triglycerides are lowered more with isotretinoin treatments alone than with combination or retinol alone treatments. Isotretinoin/retinol combinations lowered triglycerides more than retinol alone. It seems retinol may be a partial agonist of isotretinoin's activity in lowering triglycerides. Under isotretinoin treatment, isotretinoin maintains a relatively constant intracellular concentration (60 nmol/L) inside of the sebocytes.[9] Tretinoin, in contrast, rises 5 times (to 500 nmol/L) under isotretinoin treatment.[9] Under retinol treatment sebocytes' retinol concentration increases to a constant 160 nmol/L and the concentration of retinyl palmitate doubles.[9] Under the combination therapy retinoic acid levels rise to the same level as in treatment with retinoic acid alone, but the levels of retinol and retinyl palmate rise higher than under treatment with retinol alone. The inhibitory effect of isotretinoin is not affected by the presence of retinol. Isotretinoin's effects could be mediated by the constant low concentration of isotretinoin or the elevated tretinoin concentrations in sebocytes after isotretinoin treatment.

In preclinical models oral 13-cis retinoic acid, 9-cis retinoic acid, and all-trans retinoic acid have the same activity. Additionally,13-cis retinoic acid decreases sebum excretion the most, followed by 9-cis retinoic acid and alltrans retinoic acid. Only 13-cis retinoic acid shows sebosuppression.[10] Interestingly, 13-cis retinoic acid does not bind nuclear receptors.[10] Thus, either sebosuppression is not nuclear receptor mediated or 13-cis retinoic acid is first metabolized to a receptor-binder at the level of the sebaceous gland.

Retinol, retinal, and all-trans retinoic acid are inactivated by P-450 isozymes to 4-hydroxy-compounds, and 4-oxo-retinoic acid to more polar metabolites.[11] One allele of P-4501A, one of the most active P-450 isozymes that can metabolize retinoids, is overexpressed in acne patients. This isozyme may rapidly metabolize the endogenous retinoids causing a deficit of active natural retinoids, which may aid in acne causation.[11]

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