Decoding isotretinoin: Understanding mechanism of action may lead to alternative therapies

May 1, 2008

Isotretinoin is a potent therapy for treating acne, but the associated side effects and regulatory hurdles leave dermatologists increasingly reluctant to use it.

Key Points

National report - Isotretinoin is a potent therapy for treating acne, but the associated side effects and regulatory hurdles leave dermatologists increasingly reluctant to use it.

The search is on to understand its mechanism of action to develop better, safer alternative therapies.

A key element may have fallen into place with the discovery that isotretinoin upregulates the lipocalin 2 gene that encodes neutrophil gelatinase-associated lipocalin (NGAL).

Using microarray analysis of gene expression in skin samples from patients at baseline and one week after starting isotretinoin, she found that 58 genes were significantly upregulated and 27 were significantly downregulated while patients were on the drug.

The expression of many other genes changed to lesser degrees.

Among the most highly upregulated genes was lipocalin 2 (LCN2). A literature search revealed that it was associated with induced apoptosis in murine lymphocytes. It quickly became the focus of study for the Penn State University College of Medicine researcher.

Working in a human cell culture system, Dr. Thiboutot found that blocking NGAL expression stopped apoptosis cold.

"These data suggest that NGAL might be important in the mechanism of action of isotretinoin, but there could be other redundant pathways, as well," she says.

The NGAL peptide is believed to function as part of the innate immune defense by sequestering iron that is essential for the survival of bacteria.

Linked to isotretinoin

Dr. Thiboutot says researchers didn't detect NGAL in most samples of "normal" skin, and not at all in the follicles of baseline skin samples from their patients with acute acne, but did find it in those patients after using isotretinoin.

While NGAL has a negative effect on cell growth and apoptosis in the sebaceous gland, "We didn't notice apoptosis or changes in the keratinocytes on the surface of the skin," she says.

That finding makes Dr. Thiboutot optimistic that "It might be possible to selectively activate NGAL within the sebaceous gland and minimize any potential side effects to the epidermis."

She says there are three forms of the NGAL receptor - short, long, and high molecular weight - and hypothesized that perhaps expression differs by cell type.

Her lab is mapping the expression of those receptors by skin cell type and is trying to better understand which form of the receptor is mediating the effect of the specific protein generated by the LCN2 gene.

One observation in the study was a sex difference in expression of NGAL while on isotretinoin: robust in males, minuscule in females. However, the sample size was small, and she cautions against reading too much into it.

Yet at the same time, she says there are other sex-specific differences with acne in terms of incidence, severity and response to therapy. Women's acne often is affected by hormonal cycles, and women are less likely than men to have sustained remission once isotretinoin is stopped.

Additional research is needed to sort this out, she says.