Rash, photosensitivity,
erythema multiforme, and the
acute generalized exanthematous pustulosis (AGEP) are relatively uncommon adverse reactions of drugs. To date, the etiology is not well understood and individual susceptibility still remains unknown.
Amiodarone,
chlorpromazine,
amitriptyline, and
trimipramine are classified lysosomotropic as well as photosensitizing, however, they fail to trigger
rash and pruritic papules in all individuals. Lysosomotropism is a common charcteristic of various drugs, but independent of individuals. There is evidence that the individual ability to respond to external oxidative stress is crosslinked with the elongation of long-chain
fatty acids to very long-chain
fatty acids by ELOVLs. ELOVL6 and ELOVL7 are sensitive to ROS induced depletion of cellular
NADPH and insufficient regeneration via the pentose phosphate pathway and mitochondrial
fatty acid oxidation. Deficiency of
NADPH in presence of lysosomotropic drugs promotes the synthesis of
C16-ceramide in lysosomes and may contribute to emerging pruritic papules of AGEP. However, independently from a lysosomomotropic drug, severe depletion of
ATP and
NAD(P)H, e.g., by UV radiation or a potent
photosensitizer can trigger likewise the collapse of the lysosomal transmembrane
proton gradient resulting in lysosomal
C16-ceramide synthesis and pruritic papules. This kind of papules are equally present in polymorphous light eruption (PMLE/PLE) and
acne aestivalis (Mallorca
acne). The suggested model of a compartmentalized
ceramide metabolism provides a more sophisticated explanation of cutaneous drug adverse effects and the individual sensitivity to UV radiation. Parameters such as pKa and ClogP of the triggering drug, cutaneous
fatty acid profile, and
ceramide profile enables new concepts in risk assessment and scoring of AGEP as well as prophylaxis outcome.