Cerebral formation in situ of S-carboxymethylcysteine after ifosfamide administration to mice: a further clue to the mechanism of ifosfamide encephalopathy

Lerch, Stefanie; Küpfer, Adrian; Idle, Jeffrey R; Lauterburg, Bernhard H (2006). Cerebral formation in situ of S-carboxymethylcysteine after ifosfamide administration to mice: a further clue to the mechanism of ifosfamide encephalopathy. Toxicology letters, 161(3), pp. 188-94. Amsterdam: Elsevier 10.1016/j.toxlet.2005.09.002

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The clinical use of the alkylating oxazaphosphorine ifosfamide is hampered by a potentially severe encephalopathy. S-carboxymethylcysteine (SCMC), a metabolite of ifosfamide (IF), activates the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor, causes neuronal acidification, and could thus be responsible for the encephalopathy. Since the presence of SCMC in brain has not been documented following administration of IF, SCMC was measured in the brain of mice following both the individual i.p. administration of IF and SCMC. SCMC was found in a concentration of 108.2 +/- 29.7 nmol/g following IF, but was detectable at much lower levels following the administration of SCMC (21.1 +/- 21.2 nmol/g). Together with the observation that the concentration of SCMC was 10-fold higher in liver than in brain 1h after administration of SCMC, these findings suggest that the SCMC found after IF was formed in the brain in situ. The concentration of glutamic acid was similar in IF and SCMC treated animals. Methylene blue, which is used clinically to treat and to prevent IF encephalopathy, did not decrease the formation of SCMC in brain. By inhibiting monoamine oxidase activity it did, however, markedly increase the concentration of serotonin in brain which could modulate the effects of SCMC on AMPA/kainate receptors. Thus, SCMC is present in brain following the administration of IF and could contribute to the IF-associated encephalopathy by activation of AMPA/kainate receptors.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued]

UniBE Contributor:

Küpfer, Adrian Hermann; Idle, Jeffrey and Lauterburg, Bernhard

ISSN:

0378-4274

ISBN:

16229978

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:45

Last Modified:

06 Dec 2013 13:41

Publisher DOI:

10.1016/j.toxlet.2005.09.002

PubMed ID:

16229978

Web of Science ID:

000235512300003

URI:

https://boris.unibe.ch/id/eprint/18546 (FactScience: 738)

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