The cytochrome P450 (CYP) enzyme CYP26 (retinoic acid [RA] 4-hydroxylase) initiates the catabolism of all-trans RA (tRA) and limits the effects of tRA. The CYP26 enzyme acts specifically on tRA, but not 13-cis RA (isotretinoin), a retinoid used to treat severe acne. However, 13-cis RA can isomerize to tRA, which can then be metabolized by CYP26.
In healthy individuals, we assessed the variability of CYP26 enzymatic activity. We then investigated whether response to oral 13-cis RA among patients with acne correlates with variability in CYP26 expression.
In healthy individuals, we isolated microsomal fractions from the epidermis of keratome biopsy specimens and measured CYP26 enzymatic activity in untreated skin and skin treated with tRA. Enzymatic activity was determined based on rate of formation of 4-hydroxy RA (pg/min/mg microsomal protein). Using real-time polymerase chain reaction we quantified CYP26 messenger RNA induction after tRA application in patients with acne who responded or did not respond to one course of 13-cis RA.
In normal-appearing skin (N = 118), CYP26 enzymatic activity was widely variable (1-180 pg/min/mg microsomal fraction; mean 42.7 ± 3.5). Furthermore, CYP26 enzymatic activity was inducible in a dose-dependent manner in normal-appearing skin after tRA application, but not correlated with age or sex (N = 29). In patients with acne, CYP26 messenger RNA induction after 0.1% tRA application did not differ (P > .05) between patients who responded (N = 8, 587 ± 325-fold) or did not respond (N = 8, 657 ± 227-fold) to one course of 13-cis RA.
The small number of patients with acne treated with 13-cis RA was a major limitation.
Factors other than CYP26 activity may determine response to isotretinoin in acne.Le texte complet de cet article est disponible en PDF.
Key words : cytochrome, isotretinoin, retinoic acid 4-hydroxylase
Abbreviations used : CYP, mRNA, RA, RAR, RARE, RXR, tRA
| Drs Wang and Kwak contributed equally. Drs Wang and Kang accept responsibility for the scientific integrity of the work described in this article.
| Supported by grants 5T32 AR007197 (Dr Wang) and 1K24 AR02159-01 (Dr Kang) from the National Institutes of Health, Bethesda, MD; and the Babcock Research Endowment, University of Michigan, Ann Arbor.
| Conflicts of interest: None declared.