title: Inhibition of retinoic acid catabolism by minocycline: evidence for a novel mode of action?
abstract: Retinoic acid (RA) represents an essential and highly potent endogenous retinoid with pronounced anti-inflammatory properties and potent anti-acne activity, and has recently been suggested to share a common anti-inflammatory mode of action with tetracycline antibiotics. We hypothesized that tetracyclines may directly interfere with RA homeostasis via inhibition of its local cytochrome P450 (CYP450)-mediated degradation, an essential component of tightly regulated skin RA homeostasis. To test this hypothesis, we performed controlled in vitro RA metabolism assays using rat skin microsomes and measured RA levels in a RA-synthesizing human keratinocyte cell line, both in the presence and in the absence of minocycline, a tetracycline popular in acne treatment. Interestingly, minocycline potently blocked RA degradation in rat skin microsomes, and strikingly enhanced RA levels in RA-synthesizing cell cultures, in a dose-dependent manner. These findings indicate a potential role for CYP-450-mediated RA metabolism in minocycline's pleiotropic mode of action and anti-acne efficacy and could account for the overlap between minocycline and RA-induced effects at the level of their molecular mode of action, but also clinically at the level of the rare side effect of pseudotumor cerebri, which is observed for both, RA and minocycline treatment.
authors: Department of Psychiatry, Section Clinical Neurobiology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Francesca
authors: F
authors: Regen
authors: Department of Psychiatry, Section Clinical Neurobiology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Martin
authors: M
authors: Hildebrand
authors: Department of Psychiatry, Section Clinical Neurobiology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Nathalie
authors: N
authors: Le Bret
authors: Department of Psychiatry, Section Clinical Neurobiology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Irmelin
authors: I
authors: Herzog
authors: Department of Psychiatry, Section Clinical Neurobiology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Isabella
authors: I
authors: Heuser
authors: Department of Psychiatry, Section Clinical Neurobiology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Julian
authors: J
authors: Hellmann-Regen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008660:Metabolism / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D023421:Models, Animal; D051381:Rats; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D014212:Tretinoin; D008911:Minocycline
keywords: Vitamin A; acne vulgaris; cytochrome p450; inflammation; minocycline; pleiotropic effects; retinoic acid; retinoic acid metabolism; retinoid signalling; tetracyclines