The involvement of cytochrome p450 (CYP) 26 in the retinoic acid metabolism of human epidermal keratinocytes.
All-trans retinoic acid (RA) levels are controlled by enzymes of the vitamin A metabolism (RDH16, RalDH2, and LRAT) and RA catabolism (CYP26 and CYP2S1). Here, the mRNA expression of these enzymes was investigated in human keratinocytes at different Ca(2+)concentrations and after exposure to RA and CYP26 inhibitors. Cellular differentiation (high Ca(2+)) increased the expression of LRAT, RDH16 and RalDH2, and decreased CYP26B1. RA (1 microM) induced CYP26A1, CYP26B1, CYP2S1, CRABPII and LRAT mRNA. The CYP26 inhibitor talarozole altered CYP26A1 and LRAT mRNA expression in a similar way as RA, increased the cellular accumulation of [(3)H]RA, and induced a punctate CRABPII staining, also observed after siRNA knock-down of CYP26B1 (but not after RA exposure). Furthermore, CYP26B1 siRNA increased the accumulation of [(3)H]RA and the CRABPII mRNA, suggesting an augmented retinoid signalling. Thus CYP26B1 appears essential for RA catabolism under physiological conditions, whereas CYP26A1 might play a greater role during RA excess.
Pavez Loriè
Elizabeth
E
Department of Medical Sciences, Dermatology and Venereology, Uppsala University, SE-751 85 Uppsala, Sweden.
Li
Hao
H
Vahlquist
Anders
A
Törmä
Hans
H
D052160:Benzothiazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D052816:Foreskin / Q000166:cytology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D014801:Vitamin A / Q000378:metabolism
D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D014230:Triazoles; C082928:retinoic acid binding protein II, cellular; D014801:Vitamin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C422564:CYP2S1 protein, human; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; D002118:Calcium; C406527:R 115866