Original article
Retinoic acid 4-hydroxylase inducibility and clinical response to isotretinoin in patients with acne

https://doi.org/10.1016/j.jaad.2009.03.013Get rights and content

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.

Limitations

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

Conclusion

Factors other than CYP26 activity may determine response to isotretinoin in acne.

Section snippets

Participants

This study was approved by the University of Michigan Medical School Institutional Review Board and conducted in accordance with the Helsinki Declaration. The study was conducted in the Program for Clinical Research in Dermatology at the University of Michigan. Written informed consent was obtained from participants before enrollment. Healthy individuals were enrolled to investigate normal CYP26 expression (N = 118) and CYP26 induction by tRA (N = 29). Healthy individuals were defined as not

CYP26 enzymatic activity is variable in normal-appearing human skin

We first assessed basal (constitutive) CYP26 enzymatic activity in normal-appearing human skin (82 men and 36 women). The age range of participants was 19 to 62 years, with a mean age of 35.9 ± 0.9 years. CYP26 enzymatic activity, as determined by formation of 4-hydroxy RA, ranged from 1 to 180 pg/min/mg total epidermal microsomal protein, with a mean level of 42.7 ± 3.5 pg/min/mg total epidermal microsomal protein (Fig 1). There was no significant difference (P = .29) in enzymatic activity

Discussion

Isotretinoin, or 13-cis RA, is the most effective medication for severe acne. Despite its use for decades, the mechanism of this drug is not fully understood. Current evidence suggests that isotretinoin may affect many of the factors involved in acne pathogenesis, such as androgenic activity, sebum production, bacteria, and inflammation. Indeed, 13-cis RA has been shown in vitro to decrease androgen production.12 Isotretinoin also decreases sebocyte proliferation and differentiation, and more

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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.

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