Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?

Abstract 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, amitriptyl...

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Autores principales:	Markus Blaess, Lars Kaiser, Oliver Sommerfeld, René Csuk, Hans-Peter Deigner
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Lysosomotropism Sphingolipid metabolism Elongation of very long-chain fatty acids Pruritic papules Pruritus Lysosome Nutritional diseases. Deficiency diseases RC620-627
Acceso en línea:	https://doaj.org/article/f379503714b545d39e2aca2961b28f0f
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spelling	oai:doaj.org-article:f379503714b545d39e2aca2961b28f0f2021-11-14T12:39:46ZDrug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?10.1186/s12944-021-01552-31476-511Xhttps://doaj.org/article/f379503714b545d39e2aca2961b28f0f2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12944-021-01552-3https://doaj.org/toc/1476-511XAbstract 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.Markus BlaessLars KaiserOliver SommerfeldRené CsukHans-Peter DeignerBMCarticleLysosomotropismSphingolipid metabolismElongation of very long-chain fatty acidsPruritic papulesPruritusLysosomeNutritional diseases. Deficiency diseasesRC620-627ENLipids in Health and Disease, Vol 20, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lysosomotropism Sphingolipid metabolism Elongation of very long-chain fatty acids Pruritic papules Pruritus Lysosome Nutritional diseases. Deficiency diseases RC620-627
spellingShingle	Lysosomotropism Sphingolipid metabolism Elongation of very long-chain fatty acids Pruritic papules Pruritus Lysosome Nutritional diseases. Deficiency diseases RC620-627 Markus Blaess Lars Kaiser Oliver Sommerfeld René Csuk Hans-Peter Deigner Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
description	Abstract 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.
format	article
author	Markus Blaess Lars Kaiser Oliver Sommerfeld René Csuk Hans-Peter Deigner
author_facet	Markus Blaess Lars Kaiser Oliver Sommerfeld René Csuk Hans-Peter Deigner
author_sort	Markus Blaess
title	Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
title_short	Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
title_full	Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
title_fullStr	Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
title_full_unstemmed	Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
title_sort	drug triggered pruritus, rash, papules, and blisters – is agep a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?
publisher	BMC
publishDate	2021
url	https://doaj.org/article/f379503714b545d39e2aca2961b28f0f
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Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?

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