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Studies on the role of deoxysphingolipids in drug induced peripheral neuropathies


Bertea-Codilà, M. Studies on the role of deoxysphingolipids in drug induced peripheral neuropathies. 2010, University of Zurich, Faculty of Medicine.

Abstract

Sphingolipids are bioactive molecules involved in various celluar processes. The first step in the de novo biosynthesis of sphingolipids is catalysed by serine palmitoyltransferaes (SPT). Mammalian SPT is composed of three subunits SPTLC1, SPTLC2 and SPTLC3.
Several missense mutations in the human SPTLC1 gene cause hereditary sensory neuropathy type 1 (HSN+). HSN1 is an autosomal dominant inherited disorder that primarly affects peripheral sensory neurons. Recently our group discovered, that the underlying mutations HSN1 alter the substrate specifity of SPT, enabling the enzyme to metabolise beside serine also alanine and glycine as alternative substrates. The condensation of palmitoyl-CoA and alanine or glycine leads to the formation of two atypical sphingolipids lack the C1-hydroxyl-group, they can not be further metabolized to complex sphingolipids or degraded by the classical pathway. They are therefore considered as “dead end”metabolites.
Interestingly DoxSA occur at greatly elevated levels in the plasma of HSN1 patients compared with healthy controls and is likely harmful to neuronal cells. Since certain drugs, including several cytostatics (paclitaxel, etoposide and thalidomide) cause peripheral neuropathy, the question here was whether they increase DoxSA generation. In human embryonal kidney cells we investigated the effect on SPT activity or DoxSA formation.
We found, that paclitaxel and thalidomide have no influence on SPT activity, whereas etoposide increases SPT activity in a concentration dependent manner. Paclitaxel and etoposide, but not thalidomide, are induced DoxSA synthesis. Thus Dox SA may play a role in the development of etoposide or paclitaxel induced neuropathy. As the next step it will be important to investigate whether treatment with these neoplastic drugs increase Dox SA concentrations in vivo.

Abstract

Sphingolipids are bioactive molecules involved in various celluar processes. The first step in the de novo biosynthesis of sphingolipids is catalysed by serine palmitoyltransferaes (SPT). Mammalian SPT is composed of three subunits SPTLC1, SPTLC2 and SPTLC3.
Several missense mutations in the human SPTLC1 gene cause hereditary sensory neuropathy type 1 (HSN+). HSN1 is an autosomal dominant inherited disorder that primarly affects peripheral sensory neurons. Recently our group discovered, that the underlying mutations HSN1 alter the substrate specifity of SPT, enabling the enzyme to metabolise beside serine also alanine and glycine as alternative substrates. The condensation of palmitoyl-CoA and alanine or glycine leads to the formation of two atypical sphingolipids lack the C1-hydroxyl-group, they can not be further metabolized to complex sphingolipids or degraded by the classical pathway. They are therefore considered as “dead end”metabolites.
Interestingly DoxSA occur at greatly elevated levels in the plasma of HSN1 patients compared with healthy controls and is likely harmful to neuronal cells. Since certain drugs, including several cytostatics (paclitaxel, etoposide and thalidomide) cause peripheral neuropathy, the question here was whether they increase DoxSA generation. In human embryonal kidney cells we investigated the effect on SPT activity or DoxSA formation.
We found, that paclitaxel and thalidomide have no influence on SPT activity, whereas etoposide increases SPT activity in a concentration dependent manner. Paclitaxel and etoposide, but not thalidomide, are induced DoxSA synthesis. Thus Dox SA may play a role in the development of etoposide or paclitaxel induced neuropathy. As the next step it will be important to investigate whether treatment with these neoplastic drugs increase Dox SA concentrations in vivo.

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Additional indexing

Item Type:Dissertation
Referees:von Eckardstein A, Hornemann T
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Language:English
Date:2010
Deposited On:23 Feb 2011 15:08
Last Modified:05 Apr 2016 14:49

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