PHOTOTOXICITY OF ENVIRONMENTAL CHEMICALS

Cutaneous chemical phototoxicity is the response of the skin to the combined effects of a chemical and sunlight. Psoralens such as xanthotoxin (8-methoxypsoralen or 8-MOP) and bergaptan (5- methoxypsoralen) are among the most commonly encountered phototoxic agents. These compounds, also known as furocoumarins, are largely derived from plant sources and are used in the treatment of a variety of skin disorders including psoriasis and vitiligo. Although it is generally assumed that the major site of action of the psoralens is the DNA, we have demonstrated that the cell membrane may in fact be a primary target. We have discovered specific, saturable, high affinity receptors for psoralens on a number of epidermal cell lines in culture. These receptors are independent of the DNA and become covalently modified following ultraviolet (UVA) light exposure. The psoralen receptor has been identified as a 22,000 dalton protein present in the membrane and cytoplasmic fractions of responsive cell types. It is the overall objective of this proposal to characterize the psoralen receptor and analyze its role in psoralen action. Our laboratory has also discovered that a specific membrane target is linked to the psoralen receptor. We have shown that photoactivated psoralen (PUVA) is a potent inhibitor of epidermal growth factor (EGF) binding and internalization. The EGF receptor is a transmembrane protein possessing intrinsic tyrosine kinase activity and is known to be involved in cell growth regulation. We have found that PUVA induces EGF receptor phosphorylation predominantly on serine residues and inhibits EGF receptor tyrosine kinase activity. It is our hypothesis that alterations in the structure and function of growth factor receptors such as the EGF receptor, and their ability to generate intracellular growth regulatory signals, underlies the biological activity o{ the psoralens. Using cellular and biochemical techniques, we will examine the interaction of the psoralens, and novel psoralen derivatives that do not interact with the DNA, with the EGF receptor. We will also analyze the effects of PUVA on EGF induced calcium mobilization, an important regulatory signal involved in cell growth. These studies will provide important clues as to the mechanism of PUVA induced phototoxicity and may lead to a better understanding of the processes involved in chemical induced skin injury.