Psoralens are naturally occurring organic compounds, specifically linear furocoumarins, found in various plants. Historically, these molecules have been utilized in medicine for thousands of years, dating back to 2000 BC in ancient Egypt and India to treat skin conditions. Psoralens are categorized by their ability to become highly reactive when exposed to specific wavelengths of light, a property known as photosensitivity. This light-activated behavior forms the basis for their modern application in photochemotherapy, where they are combined with ultraviolet light to treat several skin disorders.
The Core Mechanism of Action
Psoralens are biologically inert until activated by long-wave ultraviolet A (UVA) light (320–400 nanometers). After entering a cell, the psoralen molecule first intercalates between the base pairs of the DNA double helix, forming a “dark complex.” Once the psoralen absorbs a UVA photon, it reacts chemically with pyrimidine bases in the DNA, typically thymine. This initial reaction results in the formation of a single bond, creating a psoralen-DNA monoadduct.
The absorption of a second UVA photon by the monoadduct triggers a reaction on the opposite DNA strand. This bifunctional reaction links the psoralen molecule to both strands, resulting in an interstrand cross-link (ICL). These cross-links prevent the DNA from separating, blocking both DNA replication and transcription. This inhibitory effect on cell proliferation is the underlying mechanism used to treat diseases characterized by excessive cell growth.
Therapeutic Applications in Skin Disorders
The light-activated mechanism of psoralens is medically exploited in photochemotherapy, commonly referred to as Psoralen + UVA (PUVA) therapy. This treatment involves administering a psoralen, such as methoxsalen, orally or topically, followed by controlled exposure to UVA light in a specialized light booth. The process targets and inhibits the rapid proliferation of abnormal cells characterizing certain skin diseases.
PUVA therapy is used for severe or treatment-resistant skin conditions. Psoriasis, characterized by the rapid overgrowth of skin cells, is a primary indication, as the DNA cross-linking slows excessive cell division. The therapy also treats vitiligo by stimulating melanocytes to encourage repigmentation. Other conditions treated with PUVA include certain forms of eczema and cutaneous T-cell lymphoma (CTCL), where the resulting cell death helps manage the disease.
Natural Occurrence and Everyday Exposure
Psoralens are natural defense compounds produced by a wide variety of plants to protect against pathogens and predators. These photoreactive compounds are found primarily in the Umbelliferae (Apiaceae) family, which includes common vegetables like celery, parsley, and parsnips. They are also present in the Rutaceae family, encompassing citrus fruits such as limes and bergamot oranges, as well as in figs.
While small dietary exposure is harmless, significant contact with the sap or juice of these plants followed by sun exposure can cause phytophotodermatitis. This is a non-allergic phototoxic reaction where psoralens on the skin are activated by sunlight, leading to a delayed, painful, burn-like rash, and sometimes blistering. The resulting inflammation often leaves behind hyperpigmentation that can persist for several months.
Understanding Risks and Precautions
Despite its effectiveness, PUVA therapy carries distinct risks due to the potent DNA-damaging mechanism. The most immediate concern is severe phototoxicity, manifesting as an intense, delayed sunburn-like reaction with erythema, swelling, and bullae formation. This risk necessitates careful dosing and controlled UVA light exposure in a clinical setting.
The long-term risk of skin cancer is a serious consideration, especially with cumulative treatment doses. Psoralen-induced DNA damage can lead to mutations, increasing the risk of developing non-melanoma skin cancers, particularly squamous cell carcinoma. Patients undergoing PUVA must adhere to safety measures, including wearing specialized eye protection during and after treatment to prevent cataracts. Limiting unnecessary sun exposure for at least 24 hours after taking the medication is required to prevent accidental phototoxic reactions.