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Master's Dissertation
DOI
10.11606/D.9.2008.tde-27032008-090215
Document
Author
Full name
Melissa Medrano Gomes
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2008
Supervisor
Committee
Campa, Ana (President)
Baader, Josef Wilhelm
Oliveira, Regina Vincenzi
Title in Portuguese
Dietilamida do ácido lisérgico (LSD) e N,N-dimetiltriptamina (DMT) como substratos de peroxidases: uma possível rota de metabolização
Keywords in Portuguese
NN-dimetiltriptamina (DMT)
Alucinogênicos
Dietilamida do ácido lisérgico (LSD)
Fármacos psicotrópicos
peroxidase
Abstract in Portuguese
Após um intervalo de duas décadas, ressurgiu um novo interesse em estudos sobre alucinógenos que visam a compreensão de como estes compostos interagem com o sistema nervoso central (SNC). Sabendo-se que enzimas do tipo peroxidases estão presentes em células do tipo leucócitos, neurônios e microglia, e que, são capazes de oxidar compostos indólicos, esta, portanto, poderia representar uma rota ativa de metabolização de alucinógenos no SNC, ainda não conhecida. Nesta perspectiva, este trabalho contribui com a descrição da metabolização da dietilamida do ácido lisérgico (LSD) e da N,N-dimetiltriptamina (DMT) por peroxidase de rábano (HRP) e mieloperoxidase (MPO) proveniente de neutrófilos ativados. A formação de produtos de reação foi acompanhada por HPLC com detectores de arranjo de diodos (DAD) e fluorescência, e a identificação por espectrometria de massas (MS). Ambas as peroxidases foram capazes de metabolizar LSD a compostos que coincidem com produtos de sua metabolização in vivo, como 2-oxo-3-hidroxi-LSD (O-H-LSD) e nor-LSD, por enzimas hepáticas do complexo P450. Entretanto, um terceiro produto formado não havia sido descrito anteriormente. Apresenta como característica principal a abertura do anel indólico e foi nomeado pelo nosso grupo como N,N-dietil-7-formamido-4-metil-6-oxo-2,3,4,4a,5,6-hexahidrobenzo[f]quinolina-2-carboxamida (FOMBK). De uma maneira semelhante, HRP e MPO também metabolizaram DMT a um produto hidroxilado (OH-DMT), que possivelmente apresenta considerável ação alucinógena, e a um segundo produto nomeado N,N-dimetil-N-formil-quinuramina (DMFK). Visto que peroxidases estão presentes em diferentes tipos celulares, é razoável supor que a formação dos produtos descritos neste estudo possa ocorrer in vivo, numa possível via alternativa de metabolização de LSD e DMT ainda não descrita em humanos.
Title in English
Lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) as peroxidases substrates: a possible metabolization pathway
Keywords in English
Hallucinogen
Lysergic acid diethylamide (LSD)
NN-dimethyltryptamine (DMT)
Peroxidases
Abstract in English
After a gap of two decades a new interest in hallucinogen studies that aim the comprehension of how these compounds interact with the central nervous system (CNS) rose again. It is known that peroxidases enzymes are present in cells such as leukocytes, neurons and microglia and that they are capable of oxidizing indolic compounds. Then it could represent an active metabolization pathway for hallucinogens in the CNS, not known yet. In this perspective, this study contributed with the description of the metabolization of lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) by horseradish peroxidase (HRP) and myeloperoxidase (MPO) from activated neutrophils. The formation of the reaction products was attended by HPLC with diode array and fluorescence detectors, and the identification by mass spectrometry (MS). Both peroxidases were capable of metabolizing LSD to compounds that coincide with products from its in vivo metabolization, as 2-oxo-3-hydroxy-LSD (O-H-LSD) and nor-LSD by the liver enzymes from P450 complex. However, a third compound had not been described before. It has the opened indolic ring as main characteristic and was named by our group as N,N-diethyl-7-formamido-4-methyl-6-oxo-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carboxamide (FOMBK). In a similar way, HRP and MPO also metabolized DMT to a hydroxylated product (OH-DMT) that possibly shows a considerable hallucinogen action and to a second product named as N,N-dimethyl-N-formyl-kynuramine (DMFK). Since peroxidases are present in different cell types, it is reasonable to assume that the formation of the products described in this study may occur in vivo as well, in a possible alternative metabolic pathway for LSD and DMT that has not been described in humans yet.
 
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Publishing Date
2008-08-21
 
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