ABSTRACT
Systemic and topical glucocorticoids (GC) can cause significant adverse effects not only on the dermis, but also on epidermal structure and function. In epidermis, a striking GC-induced alteration in permeability barrier function occurs that can be attributed to an inhibition of epidermal mitogenesis, differentiation and lipid production. As prior studies in normal hairless mice demonstrated that topical applications of a flavonoid ingredient found in citrus, hesperidin, improve epidermal barrier function by stimulating epidermal proliferation and differentiation, we assessed here whether its topical applications could prevent GC-induced changes in epidermal function in murine skin and the basis for such effects. When hairless mice were co-treated topically with GC and 2% hesperidin twice-daily for 9 days, hesperidin co-applications prevented the expected GC-induced impairments of epidermal permeability barrier homoeostasis and stratum corneum (SC) acidification. These preventive effects could be attributed to a significant increase in filaggrin expression, enhanced epidermal ß-glucocerebrosidase activity and accelerated lamellar bilayer maturation, the last two likely attributable to a hesperidin-induced reduction in stratum corneum pH. Furthermore, co-applications of hesperidin with GC largely prevented the expected GC-induced inhibition of epidermal proliferation. Finally, topical hesperidin increased epidermal glutathione reductase mRNA expression, which could counteract multiple functional negative effects of GC on epidermis. Together, these results show that topical hesperidin prevents GC-induced epidermal side effects by divergent mechanisms.
Subject(s)
Clobetasol/adverse effects , Clobetasol/antagonists & inhibitors , Epidermis/drug effects , Glucocorticoids/adverse effects , Glucocorticoids/antagonists & inhibitors , Hesperidin/administration & dosage , Administration, Topical , Animals , Cell Proliferation/drug effects , Clobetasol/administration & dosage , Epidermis/pathology , Epidermis/physiopathology , Female , Filaggrin Proteins , Glucocorticoids/administration & dosage , Glutathione Reductase/genetics , Intermediate Filament Proteins/genetics , Lipid Metabolism/drug effects , Mice , Mice, Hairless , Mice, Inbred C57BL , RNA, Messenger/genetics , RNA, Messenger/metabolism , Up-Regulation/drug effectsABSTRACT
Cytochrome P4501A1 is known to be expressed in skin and thus has been implicated in the pathogenesis of skin cancer due to certain environmental carcinogens. Retinoic acid (RA) has been used in chemoprevention of certain skin and other epithelial cancers. Therefore, we used Northern and Western analysis to determine the effect of externally applied RA on basal P4501A1 expression. RA reduced basal levels of P4501A1 mRNA and protein by 68 (n = 14, P = 0.005) and 75% (n = 7, P = 0.04) respectively. RA application also reduced basal levels of P4501A2 (another P4501A1 subfamily member) mRNA by 93% (n = 7, P = 0.001) as determined by reverse transcription-polymerase chain reaction. Interestingly, P4501A1 mRNA expression induced by coal tar or glucocorticoid (clobetasol) was reduced 46 (n = 10, P = 0.003) and 69% (n = 5, P < 0.05) respectively by RA co-application. Downregulation of basal P4501A1 expression and antagonism of coal tar mediated P4501A1 induction by RA may be a mechanism involved in chemo-prevention of skin and other epithelial cancer by RA.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Keratinocytes/drug effects , Tretinoin/pharmacology , Adult , Cells, Cultured , Clobetasol/antagonists & inhibitors , Clobetasol/pharmacology , Coal Tar/pharmacology , Cytochrome P-450 Enzyme System/biosynthesis , Cytochrome P-450 Enzyme System/genetics , Enzyme Induction , Humans , Keratinocytes/cytology , Keratinocytes/enzymology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tretinoin/metabolismABSTRACT
RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a synthetic steroid receptor antagonist. To evaluate the peripheral antiglucocorticoid action of this compound, we investigated its ability to antagonize cutaneous steroid-induced vasoconstriction. This phenomenon, produced by three different topical steroids in six normal men, was consistently and significantly attenuated or abolished by oral administration of 6 mg/kg RU 486. This demonstration of a peripheral action of RU 486 is important in relation to the potential therapeutic use of this well tolerated drug in states of hypercortisolism. It also indicates that the cutaneous vasoconstrictor effects of topical steroids are mediated by occupancy of glucocorticoid receptors.
