Expression of retinoid-regulated genes in lamellar ichthyosis vs. healthy control epidermis: changes after oral treatment with liarozole.
Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is liarozole, which blocks the cytochrome P450 (CYP26)-mediated catabolism of endogenous all-trans retinoic acid. This study focuses on the expression of retinoid-related genes in ichthyotic epidermis before and after treatment with oral liarozole. We first compared the mRNA expression of cellular retinoic acid binding protein II (CRABPII), keratin (KRT) 2 and 4, CYP26A1 and B1, and two markers of inflammation (interleukin-1alpha and tumours necrosis factor (TNF)-alpha) in shave biopsies from 11 genetically defined, untreated patients and 12 age- and sex-matched healthy controls, finding no overt differences between the groups, besides elevated CRABPII expression. We then studied the biomarkers before and after 4 weeks of treatment with liarozole (75 or 150 mg/day), which produced a better therapeutic response in patients with Ichthyin (n=3) than in those with TGM1 (n=6) mutations. A significant decrease in the mRNA expression of KRT2 and TNF-alpha, and trends toward increased expression of KRT4 and CYP26A1 were observed in liarozole-treated patients, consistent with an increased retinoid stimulation of epidermis. However, there were no dose-related responses and the results of the immunostaining did not always parallel the mRNA findings. The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis.
Pavez Loriè
Elizabeth
E
Department of Medical Sciences/Dermatology, Uppsala University, Uppsala, Sweden.
Gånemo
Agneta
A
Borgers
Marcel
M
Wouters
Luc
L
Blockhuys
Stan
S
van de Plassche
Lieve
L
Törmä
Hans
H
Vahlquist
Anders
A
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D003879:Dermatologic Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000188:drug therapy* / Q000235:genetics*; D007093:Imidazoles / Q000008:administration & dosage*; D053582:Interleukin-1alpha / Q000032:analysis; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012867:Skin / Q000737:chemistry; D014212:Tretinoin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015415:Biomarkers; D003879:Dermatologic Agents; D007093:Imidazoles; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014409:Tumor Necrosis Factor-alpha; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; C061121:liarozole