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Carcinogenesis Advance Access published online on March 7, 2006
Carcinogenesis, doi:10.1093/carcin/bgi367
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received September 2, 2005
Revised November 12, 2005
Accepted February 11, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Photoprotective effect of isoflavone genistein on ultraviolet B induced pyrimidine dimer formation and PCNA expression in human reconstituted skin and its implications in dermatology and prevention of cutaneous carcinogenesis

Julian O. Moore 1, Yongyin Wang 2, William G. Stebbins 2, Dayuan Gao 2, Xueyan Zhou 2, Robert Phelps 3, Mark Lebwohl 2, and Huachen Wei 2 *

1 Department of Dermatology, Mount Sinai School of Medicine, New York, New York, USA; Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York, USA
2 Department of Dermatology, Mount Sinai School of Medicine, New York, New York, USA
3 Department of Dermatology, Mount Sinai School of Medicine, New York, New York, USA; Department of Dermatopathology, Mount Sinai School of Medicine, New York, New York, USA

* To whom correspondence should be addressed.
Huachen Wei, E-mail: huachen.wei{at}mssm.edu


  Abstract

Genistein, the most abundant isoflavone of the soy derived phytoestrogen compounds is a potent antioxidant and inhibitor of tyrosine kinase. We previously reported the antiphotocarcinogenic effects of genistein in SKH-1 murine skin, including its capacity for scavenging reactive oxygen species, inhibiting photodynamic DNA damage, and down regulating UVB-induced signal transduction cascades in carcinogenesis. In this study we elucidate genistein's photoprotective efficacy within the context of full thickness human reconstituted skin relative to acute challenges with ultraviolet-B irradiation. Skin samples were pre-treated with 3 concentrations of genistein (10, 20, and 50 µM) 1hr. prior to UVB radiation at 20 and 60 mJ/cm2. Proliferating cell nuclear antigen (PCNA) and pyrimidine dimer (PD) expression profiles were localized using immunohistochemical analysis on paraffin embedded samples six and twelve hours post UVB exposure. Genistein dose dependently preserved cutaneous proliferation and repair mechanics at 20 and 60 mJ/cm2, as evidenced by the preservation of proliferating cell populations with increasing genistein concentrations, and noticeable paucity in PCNA immunoreactivity in the absence of genistein. Genistein inhibited UV-induced DNA damage, evaluated with PD immunohistochemical expression profiles, which demonstrated an inverse relationship with increasing topical genistein concentrations. Irradiation at 20 and 60 mJ/cm2 substantially induced PD formation in the absence of genistein, and a dose dependent inhibition of UVB induced PD formation was observed relative to increasing genistein concentrations. Collectively all genistein pre-treated samples demonstrated appreciable histologic architectural preservation when compared with untreated specimens. These findings represent a critical link between our animal and cell culture studies with those of human skin, and represent the first characterization of the dynamic alterations of UV-induced DNA damage and proliferating cell populations relative to pre treatment with genistein in human reconstituted skin. The implications of our findings serve as compelling validation to our conclusions that genistein may serve as a potent chemopreventive agent against photocarcinogenesis.

Keywords: Genistein; Human skin equivalent; UVB; DNA damage; DNA repair; Immunohistochemistry.
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