Mutagenesis by 8-methoxypsoralen and 5-methylangelicin photoadducts in mouse fibroblasts: mutations at cross-linkable sites induced by offoadducts as well as cross-links.
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 lambda 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.
Gunther
E J
EJ
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8040.
Yeasky
T M
TM
Gasparro
F P
FP
Glazer
P M
PM
D000818:Animals; D001483:Base Sequence; D005347:Fibroblasts; D011564:Furocoumarins / Q000633:toxicity*; D008730:Methoxsalen / Q000633:toxicity*; D051379:Mice; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity*; D011701:PUVA Therapy / Q000009:adverse effects*; D010777:Photochemistry
D011564:Furocoumarins; D009153:Mutagens; C023026:5-methylangelicin; D008730:Methoxsalen