By Abby Van Voorhees, MD, December 01, 2011
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Angela Tewari, MBBS, about her recent Journal of Investigative Dermatology article, “UVA1 Induces Cyclobutane Pyrimidine Dimers but Not 6-4 Photoproducts in Human Skin In Vivo.”
Dr. Van Voorhees: Tell us a little about what is known about UVB and UVA radiation. Which is thought to be the main carcinogen contributing to the risk of skin cancer?
Dr. Tewari: The sun emits UVB (≤5 percent) and UVA (≥95 percent), which can be divided into UVA1 (340-400 nm) and UVA2 (320-340 nm). UVA1 makes up 75 percent of the ultraviolet radiation (UVR) that reaches us. DNA primarily absorbs in the UVB waveband (280-320 nm) but also absorbs some UVA (315-400nm). Most human studies have examined the effects of UVB on the skin and found that it induced particular types of DNA damage, called cyclobutane pyrimidine dimers (CPD) and 6-4pyrimidine-pyrimidone photoproducts (6-4PP). These lesions, if not repaired, can lead to skin cancer. Recent studies have shown that UVA1 produces more CPD than the expected oxidative damage to DNA, which has long been thought to be the most important way by which UVA causes damage to cells.
However, UVB is the main cause of non-melanoma skin cancer. We know less about the spectral dependence for melanoma, but some data suggest that UVA is relatively more important in melanoma in comparison with non-melanoma skin cancers.
Dr. Van Voorhees: What happens to the skin when it has been exposed to UVB at high doses? What is the “UVB signature?”
Dr. Tewari: Low UVB doses that do not result in redness (sunburn) readily induce CPD. Increased doses result in more CPD. These lesions may result in potentially carcinogenic mutations, known as the UVB signature mutations (C to T and CC to TT transitions) because they are often found in non-melanoma skin cancers. (See a diagram of how these mutations are formed.)[pagebreak]
Dr. Van Voorhees: That’s quite interesting. It sounds like you’re saying that all quantities of UVB can cause damage, and that even the lower doses that don’t cause phototoxicity can lead to CPDs, while higher doses that do cause erythema lead to even more CPDs.
What about UVA? What is the effect of UVA radiation? Is there a comparable UVA signature? How is this similar to UVB? How does it differ?
Dr. Tewari: UVA can cause direct damage to DNA (i.e., formation of CPD), but also damages DNA via the formation of reactive oxygen species (ROS) that cause oxidation of its bases particularly guanine resulting in the formation of 8-oxoguanine. This can result in characteristic mutations — G to T transversions and T to G transversions during DNA replication. These are known as UVA signature mutations, but are not thought to be as mutagenic as the UVB signature mutation arising from CPD. (See a diagram of how these mutations are formed.)
Dr. Van Voorhees: Tell us about your experiments. Why were MEDs (minimal erythema doses) chosen?
Dr. Tewari: The MED is the minimal dose needed to give a just-perceptible erythema on the skin. Multiples of MED, with the different UV spectra, were used to give comparable levels of erythema and hence biological activity. This was a way of standardizing the effects of UVB and UVA exposure doses to give equal amounts of erythema/inflammation. Furthermore, the MED is widely used as an exposure unit in photodermatology.[pagebreak]
Dr. Van Voorhees: Was there a correlation between a patient’s UVB MED and their UVA MED? What does this suggest?
Dr. Tewari: No, there was no correlation, which means that their mechanisms of induction are probably different. An earlier study by another group showed that UVA erythema was oxygen-dependent, which is not the case with UVB. There is no connection between how high your UVA MED and your UVB MED are.
Dr. Van Voorhees: Was there a difference in photoproducts formed as a result of this exposure? Were they identified in similar or different areas of the skin? Depth of skin?
Dr. Tewari: There was a considerable difference in type and amount of photoproducts formed. UVB produced CPD and 6-4PP products. These were both more pronounced in the upper epidermis than lower epidermis. There were even fewer in the dermis.
UVA1 only produced CPDs, but these were three to four times less frequent than UVB for a given MED multiple. These were more pronounced at the basal epidermis and dermis. Although UVB at erythemally equivalent doses always produced more CPD than UVA1, the levels were quite similar at the basal epidermis with both sources.
Dr. Van Voorhees: What can we extrapolate from these studies? Is UVA more of a carcinogen than previously understood? Do we understand the damage caused by UVA when the dose is less than that which causes erythema? As you know this is often the clinical situation for those who utilize tanning salons. Are there take-away messages we should be sharing with our patients?
Dr. Tewari: Although the thymine dimer lesions that we measured are not very mutagenic, they are indicative of other types of UVA1-induced lesions that have strong mutagenic potential. The basal epidermis is where the actively dividing stem cells reside and hence if UVA1 is producing relatively more damage here this is more worrying for potential further consequences, especially as the level of UVB- and UVA1-induced damage at the basal layer was approximately similar. We also observed damage with sub-erythemal exposures.
UVA1 is the predominant waveband of tanning lamps, the use of which has been shown to be associated with malignant melanoma. Melanocytes are located in the basal epidermis and thus may be very susceptible to UVA1-induced damage. We should be telling our patients to avoid tanning beds and use fake [rub-on or spray] tanning instead.
Dr. Tewari is a dermatologist in training conducting skin science research in photobiology at St John’s Institute of Dermatology in the division of genetics and molecular medicine at King’s College London School of Medicine. Her article was published online in the Journal of Investigative Dermatology, on Oct. 6, 2011. doi:10.1038/jid.2011.283.