Volume 37, Issue 8, Page 36 (August 2006)

LESLIE S. BAUMANN, M.D.

DR. BAUMANN is director of cosmetic dermatology at the University of Miami. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at our editorial offices via e-mail at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

As with the antioxidant resveratrol, most data on the health benefits of the thiol N-acetylcysteine have come to light in just the past few years. Unlike resveratrol, though, N-acetylcysteine cannot be obtained through the diet. This cell-permeable, water-soluble compound is derived from the amino acid L-cysteine and acts as a precursor to the endogenous antioxidant glutathione.

N-acetylcysteine (NAC) is considered a potent antioxidant with a budding reputation for scavenging reactive oxygen species and protecting against toxic chemical exposure (Int. J. Toxicol. 2004;23:239–47). Consequently, its potential role in retarding or preventing any stage of carcinogenesis and photoaging is most relevant for consideration in dermatologic applications.

In one of the earlier reports connecting chemoprevention and NAC, the thiol was shown to significantly decrease the proliferative index of colon carcinogenesis while a placebo showed no change (Cancer Lett. 1999;147:109–14). In an in vitro study, researchers used primary human epidermal keratinocytes and the human keratinocyte cell line HaCaT to evaluate the effects of UVB on interleukin-18 production (which positively correlates with skin cancer). Interleukin-18 production was enhanced by UVB in a dose- and time-dependent fashion, but NAC interfered with the UVB effects (Biochem. Biophys. Res. Commun. 2002;298:289–95).

Anticarcinogenesis

NAC has demonstrated activity against the effects of other UV wavelengths as well. A recent study compared NAC and ascorbic acid, administered individually or combined in drinking water, on the carcinogenicity of UVC-filtered halogen lamps in SKH-1 hairless mice. It took 300 days of exposure before the first lesions appeared, with NAC extending latency by 90 days. The incidence and multiplicity of UVC-induced tumors also were significantly lowered, tumor size was reduced, and squamocellular carcinomas were prevented in the NAC group. Ascorbic acid, which can exhibit some prooxidant activity, had the opposite effect. However, when NAC was administered in combination with ascorbic acid, the adverse effects of vitamin C were significantly diminished (Carcinogenesis 2005;26:657–64).

NAC's potential in disrupting carcinogenesis was shown when it successfully reduced the level of reactive oxygen species in dermal fibroblasts. This activity prevented tumor cell-derived transforming growth factor-ß1 mediated downregulation of intercellular communication between confluent fibroblasts (Biochem. Biophys. Res. Commun. 2004;319:321–6).

NAC has also been shown to inhibit platelet-induced increases of the mitogenic rate in human fibroblasts (Eur. J. Cell Biol. 2003;82:565–71).

Light and Heat Protection

Using an ex vivo pigskin explant model, investigators showed that NAC was one among three water-soluble antioxidants to protect against UVA-induced decomposition of the nonsteroidal anti-inflammatory drug (NSAID) suprofen. Increased levels of suprofen and lower levels of photoproducts were found in antioxidant-treated skin, and such findings were dose-dependent. The researchers concluded that NAC, and the other antioxidants, scavenged the free radicals and reactive oxygen species engendered by the exposure of the NSAID to UVA (Photochem. Photobiol. 2003;77:343–8).

In another study, researchers evaluated the effects of NAC on cultured human fibroblasts during protracted exposure to artificial UV and visible irradiation. Incubation of skin and lung fibroblasts at 37° C for 1 hour before light exposure resulted in less DNA damage in both types of cells as well as a delay in the onset of such damage. The authors concluded that their results buttress previous evidence that NAC protects cells directly via scavenging UV-induced reactive oxygen species and indirectly via its role in synthesizing the potent antioxidant glutathione (J. Photochem. Photobiol. B 2003;72:55–60).

In an investigation of the ability of UV radiation to produce reactive oxygen species in human skin in vivo and the potential of genistein and NAC to hinder such responses, researchers found that pretreatment with NAC inhibited extracellular signal-regulated kinase, UV-induced cJun protein, and induction of the cJun-driven enzyme collagenase. No effects on erythema were noted.

Recently, an in vivo experiment assessing the effects of heat on the expression of elastic fiber (tropoelastin and fibrillin-1) and matrix metalloproteinase-12 in human skin revealed that pretreatment with NAC or genistein 24 hours before heat exposure hampered heat-induced expression of tropoelastin. Although fibrillin-1 expression was not affected, the data from this study, given the role of amassed elastotic material in photoaging, support the evidence that NAC has a potential role in skin protection (J. Invest. Dermatol. 2005;124:70–8).

In an earlier in vivo study, pretreatment of human skin with NAC inhibited UV-induced macrophage metalloelastase expression, suggesting that macrophage metalloelastase may be an important factor in solar elastosis, the authors noted (J. Invest. Dermatol. 2002;119:507–12).

Dietary and Long-Term Effects

In a study with implications for protection against dermal and systemic chemical pollutants, investigators evaluated the long-term effects of oral NAC administration in 20 Sprague-Dawley rats (10 females, 10 males) over 30 days. They looked at organ histopathology and tissue glutathione (GSH) as well as total glutathione S-transferase (GST) activity levels. Negative controls received deionized water in the same dosages. Day 30 measurements revealed significantly higher GST activity and tissue GSH concentration in the test animals than in controls. No lesions were associated with NAC administration, as determined by histopathologic assessment. The authors concluded that more research is needed to ascertain whether the elevated GST and GSH readings accurately reflect chemoprotection conferred by NAC against orally ingested or topical chemical toxins (Int. J. Toxicol. 2004;23:239–47).

Indeed, orally administered NAC has demonstrated promising results. In one study, investigators fed p53 haploinsufficient Tg.AC (v-Ha-ras) mice, which quickly develop chemically induced skin tumors, a basal diet with or without 3% NAC before and after topically applying the carcinogen benzo[a]pyrene (twice a week for 7 weeks). The regimen was continued until at least one lesion could be observed in 50% of mice within a group. Then, the other diet was administered to half of each group.

NAC was found to induce a delay in tumor formation and reduce tumor multiplicity (reduction of tumors by 38% in the NAC-supplemented group, 26% in those switched from the NAC-supplemented diet to the basal, and 15% in those switched from basal to NAC) (Nutr. Cancer 2002;43:59–66).

Researchers also investigated long-term therapy with various antioxidants (NAC, taurine, a combination of NAC and taurine, and oxerutin) for the treatment of chronic experimental streptozocin-induced diabetes in rats. They found that NAC combined with taurine, as well as oxerutin, diminished the accumulation of collagen-linked fluorescence in skin, compared with untreated diabetic rats (Diabetes 2003;52:499–505).

In addition, investigators studied long-term oral administration of NAC along with the antioxidant a-lipoic acid as adjuvant therapy (to subcutaneous recombinant interleukin-2 and medroxyprogesterone acetate) for patients with solid tumors whose previous chemotherapy resulted in an objective response or disease stabilization. The drug combination exhibited very low toxicity while enhancing biologic markers of patient outcome (Oncol. Rep. 2002;9:887–96).

NAC has even been shown to prevent hair loss in guinea pigs exposed intratracheally to subacute doses of the mustard analogue 2-chloroethyl ethyl sulfide (J. Biochem. Mol. Toxicol. 2004;18:150–3).

Despite the relative dearth of data pertaining to dermatologic applications of NAC, copious evidence suggests the antioxidant potency of this thiol. As a precursor to glutathione, NAC's primary function is protecting the liver by aiding in the elimination of toxins. It is used most frequently as an oral supplement, but is appearing more and more as an ingredient in unregulated topical formulations. Much more research is needed to determine how readily applicable NAC is in the dermatologic armamentarium, but preliminary results are promising.

PII: S0037-6337(06)71472-3

doi:10.1016/S0037-6337(06)71472-3

© 2006 Elsevier Inc. All rights reserved.