Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases.
BACKGROUND
Treatment of common skin diseases such as psoriasis is complicated by differences between individuals in response to topical drug treatment and photochemotherapy. Individuality in hepatic expression of drug-metabolising enzymes is an important determinant of systemic drug handling; we investigated whether similar variation in cutaneous gene expression contributes to individuality in response to topical therapies.


METHODS
We used quantitative real-time RT-PCR to demonstrate the expression in skin of a recently identified cytochrome P450, CYP2S1, in healthy volunteers (n=27) and patients with psoriasis (n=29). We also investigated regulation of CYP2S1 by ultraviolet radiation, psoralen-ultraviolet A (PUVA), and topical drugs used to treat psoriasis.


RESULTS
We found that CYP2S1 is expressed in skin and showed pronounced individuality in constitutive expression of the enzyme and its induction after ultraviolet irradiation or topical drug treatment. Cutaneous expression of CYP2S1 was induced by ultraviolet radiation, PUVA, coal tar, and all-trans retinoic acid; expression was significantly higher in lesional psoriatic skin than in adjacent non-lesional skin (geometric mean 3.38 [95% CI 2.64-4.34] times higher; p<0.0001), which implies that topical drugs are differentially metabolised in psoriatic plaque and non-lesional skin. We showed that all-trans retinoic acid is metabolised by CYP2S1, which has higher cutaneous expression than CYP26, previously described as the specific cutaneous P450 retinoic-acid-metabolising enzyme.


CONCLUSIONS
These findings increase our understanding of the interaction between therapeutic agents and the skin and suggest a functional role for CYP2S1 in the metabolism of topical drugs and in mediating the response to photochemotherapy in psoriasis.
Smith
Gillian
G
Biomedical Research Centre, Ninewells Hospital and Medical School, DD1 9SY, Dundee, UK.
Wolf
C Roland
CR
Deeni
Yusuf Y
YY
Dawe
Robert S
RS
Evans
Alan T
AT
Comrie
Muriel M
MM
Ferguson
James
J
Ibbotson
Sally H
SH
D003033:Coal Tar / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004790:Enzyme Induction / Q000187:drug effects / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D010105:Oxygenases / Q000235:genetics*; D011701:PUVA Therapy; D016133:Polymerase Chain Reaction; D011565:Psoriasis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000201:enzymology* / Q000473:pathology; D014212:Tretinoin / Q000378:metabolism / Q000627:therapeutic use; D014467:Ultraviolet Therapy
D012333:RNA, Messenger; D014212:Tretinoin; D003033:Coal Tar; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C422564:CYP2S1 protein, human