Retinoic acid 4-hydroxylase inducibility and clinical response to isotretinoin in patients with acne.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
The small number of patients with acne treated with 13-cis RA was a major limitation.


CONCLUSIONS
Factors other than CYP26 activity may determine response to isotretinoin in acne.
Wang
Frank
F
Department of Dermatology, University of Michigan Medical School, 1618 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0314, USA. frawang@med.umich.edu
Kwak
Heh Shin R
HS
Elbuluk
Nada
N
Kaczmarek
Anya L
AL
Hamilton
Ted
T
Voorhees
John J
JJ
Fisher
Gary J
GJ
Kang
Sewon
S
D000152:Acne Vulgaris / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D015474:Isotretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D000072516:Retinoic Acid 4-Hydroxylase; D012307:Risk Factors; D012680:Sensitivity and Specificity; D046509:Tissue Culture Techniques
D015415:Biomarkers; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D015474:Isotretinoin