Effects of azelaic acid on proliferation and ultrastructure of mouse keratinocytes in vitro.
The effects of azelaic acid (C9-dicarboxylic acid, AZA) on the proliferation and ultrastructure of neonatal NMRI mouse keratinocyte cultures were studied to clarify the mechanisms of AZA action on normal and diseased epidermis. The dose- and time-dependency of the drug effects on DNA synthesis was examined by 3H-thymidine incorporation into DNA and by autoradiography. Electron microscopy was used to detect the target cell organelles of the drug. Azelaic acid decreased DNA synthesis in a dose- and time-dependent manner with a 50% inhibitory concentration of 20 mM. The inhibition of DNA synthesis was already observed after 1 h of treatment, reached its maximum after 4 h, and was stable for 24 h. A complete reversibility of the inhibitory effects was observed within 2 h after discontinuation of the treatment, and, interestingly, a rebound effect occurred with a temporary increase of DNA synthesis. Furthermore, treatment with AZA reduced the RNA and protein synthesis of the cells. Electron microscopic evaluation of treated cultures showed early marked damage of the mitochondria, followed by dilation of the rough endoplasmic reticulum (RER). These alterations were completely reversible after discontinuation of the treatment. Our findings show that AZA exerts a dose- and time-dependent, reversible antiproliferative effect on keratinocytes, acting primarily on mitochondria and RER. The antiproliferative action of AZA could explain its beneficial effect in some skin disorders characterized by alteration of keratinocytic differentiation.
Detmar
M
M
Department of Dermatology, University Medical Center Steglitz, Free University of Berlin, Federal Republic of Germany.
Mayer-da-Silva
A
A
Stadler
R
R
Orfanos
C E
CE
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007633:Keratins; D051379:Mice; D008854:Microscopy, Electron; D009994:Osmolar Concentration; D013997:Time Factors
D003998:Dicarboxylic Acids; D007633:Keratins; D004247:DNA; C010038:azelaic acid