Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis.
BACKGROUND
An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all-trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866).


OBJECTIVE
To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial.


METHODS
Gels containing talarozole (0.35% or 0.07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1alpha and tumour necrosis factor-alpha].


RESULTS
Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1alpha compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected.


CONCLUSIONS
Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.
Pavez Loriè
E
E
Department of Medical Sciences/Dermatology, Uppsala University, SE-751 85 Uppsala, Sweden.
Cools
M
M
Borgers
M
M
Wouters
L
L
Shroot
B
B
Hagforsen
E
E
Törmä
H
H
Vahlquist
A
A
D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D012176:Retinoids / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
D052160:Benzothiazoles; D015415:Biomarkers; D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014230:Triazoles; C082928:retinoic acid binding protein II, cellular; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D050697:Retinal Dehydrogenase; C406527:R 115866