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Mutagenesis by 8-Methoxypsoralen and 5-Methylangelicin Photoadducts in Mouse Fibroblasts: Mutations at Cross-Linkable Sites Induced by Monoadducts as well as Cross-Links¹

Departments of Therapeutic Radiology [E. J. G., T. M. Y., P. M. G.] and Dermatology [F. P. G.], Yale University School of Medicine, New Haven, Connecticut 06520-8040

Psoralens are used clinically in the treatment of several skin diseases, including psoriasis, vitiligo, and cutaneous T cell lymphoma. However, psoralen treatment has been associated with an increased risk of squamous cell carcinoma of the skin. To elucidate molecular events that may play a role in the psoralen-related carcinogenesis, we examined psoralen-induced mutagenesis in a mouse fibroblast cell line carrying a recoverable, chromosomally integrated phage shuttle vector. Using the supF gene as a mutation reporter gene, we determined the spectrum of mutations induced by photoactivation of 8-methoxypsoralen and of 5-methylangelicin. Both psoralens generated predominately T:A to A:T and some T:A to G:C transversions. Most of the mutations occurred at either 5' TpA or 5' ApT sites, both of which are conducive to interstrand cross-link formation. However, 5-methylangelicin produces only monoadducts, whereas 8-methoxypsoralen generated 20% cross-links and 80% monoadducts under the conditions of our experiments, as measured by direct HPLC analysis of the DNA from the treated cells. Although most of the mutations occurred at potentially cross-linkable sites, these results implicate monoadducts, as well as cross-links, as critical premutagenic lesions in psoralen-treated mammalian cells. These findings may help in the identification of carcinogenic changes induced by psoralen, and they may aid in the improved design of psoralen-based treatment regimens in the future.

¹ This work was supported by grants from the Charles E. Culpeper Foundation, Leukemia Society of America, NIH (ES05775, P. M. G.), and Yale Skin Disease Research Center (F. P. G., P. M. G.). We also acknowledge support from Therakos, Inc. (F. P. G.).

² To whom requests for reprints should be addressed, at Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040.

Received 10/14/94. Accepted 1/19/95.

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