Reversal of UVA Skin Photosensitivity and DNA Damage in Kidney Transplant Recipients by Replacing Azathioprine

Abstract

Azathioprine is associated with enhanced skin photosensitivity to ultraviolet A (UVA) and leads to incorporation of 6-thioguanine (6-TG) into DNA of dividing cells. Unlike canonical DNA, 6-TG DNA is damaged by UVA, which comprises more than 90% of the ultraviolet reaching earth. Skin photosensitivity to UVA and UVB was measured in 48 kidney transplant patients immunosuppressed either by azathioprine (n = 32) or mycophenolate (n = 16). In 23 patients, azathioprine was subsequently replaced by mycophenolate and skin photosensitivity, DNA 6-TG content in peripheral blood mononuclear cells, and susceptibility to UVA-induced DNA damage were monitored for up to 2 years. The mean minimal erythema dose to UVA on azathioprine was twofold lower than on mycophenolate. Three months after replacing azathioprine by mycophenolate mofetil, the minimal erythema dose to UVA had increased from 15 to 25 J/cm 2 (p < 0.001) accompanied by reduced DNA 6-TG content. P53 protein expression in irradiated skin indicated reduced susceptibility to UVA-induced DNA damage. 6-TG DNA in peripheral blood mononuclear cells remained measurable for over 2 years. Replacing azathioprine selectively reduced the skin photosensitivity to UVA, attenuated UVA-induced skin DNA damage, and is likely based on incorporated 6-TG in DNA.

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

“…Notably, the effect of TBE-31 on 6-TG incorporation in DNA of dorsal skin is larger than the local effect on MRP4, implying that, in addition to MRP4, there are other (presently unidentified) contributing factors. Most importantly, because of the direct link between 6-TG incorporation in DNA and increased skin photosensitivity to UVA radiation (25,28,33), the ability of TBE-31 to decrease the levels of 6-TG in skin DNA is expected to lower one of the main risk factors for skin cancer development associated with thiopurine therapies.…”

“…Although immunosuppression, in general, is a risk factor for skin cancer development, the use of one of the most commonly prescribed thiopurines, azathioprine, is causally related to increased sensitivity of the human skin to UVA radiation, which comprises more than 90% of the incident solar UV radiation. This direct relationship was recently shown by the observed reversal of UVA-mediated skin photosensitivity and DNA damage in renal transplant recipients by replacing azathioprine with mycophenolate mofetil (25). Nonetheless, the use of thiopurines in organ transplantation, as well as in the management of inflammatory and autoimmune diseases, is anticipated to continue, as they are highly effective and generally well tolerated (20).…”

Immunsuppressive legemidler og utvikling av hudkreft etter organtransplantasjon

“…Dette tyder på at azatioprin kan gi hudkreft gjennom DNA-skade i huden. Transplanterte pasienter som skifter ut azatioprin med mykofenolat, får normalisert sin fotosensitivitet overfor UV-stråling og får mindre UV-indusert DNA-skade i huden (33).…”

Phototherapie und Karzinogenese

“…Weniger gut beschrieben ist die häufiger verwendete Substanz Azathioprin, die die Lichtempfindlichkeit der Haut für UVA verdoppelt und einen direkten Schaden der DNS durch UVA ermöglicht [30]. Kürzlich konnten wir zeigen, dass nicht nur die Lichtempfindlichkeit der Haut bei Patienten unter Azathioprin steigt, sondern dass UVA auch zu vermehrtem Genschaden der Keratinozyten führt, ein Zustand, der durch einen Wechsel der Medikation messbar gebessert werden konnte [16]. [39], wobei diese in der Vorgeschichte auch mit Teerpräpara-ten behandelt worden waren.…”