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Forensic Toxicology

, Volume 30, Issue 2, pp 87–97 | Cite as

Oxidation of lysergic acid diethylamide (LSD) by peroxidases: a new metabolic pathway

  • Melissa M. Gomes
  • Felipe A. Dörr
  • Luiz H. Catalani
  • Ana Campa
Original Article

Abstract

Lysergic acid diethylamide (LSD) is a potent hallucinogen that is primarily metabolized to 2-oxo-3-hydroxy-LSD (O-H-LSD) and N-desmethyl-LSD (nor-LSD) by cytochrome P450 complex liver enzymes. Due to its extensive metabolism, there still is an interest in the identification of new metabolites and new routes of its metabolism in humans. In the present study, we investigated whether LSD could be a substrate for horseradish peroxidase or myeloperoxidase (MPO). Using liquid chromatography coupled to UV detection and electrospray ionization mass spectrometry (LC-UV–ESI–MS), we found that both peroxidases were capable of metabolizing LSD to the same compounds that have been observed in vivo (i.e., O-H-LSD and nor-LSD). In addition, we found another major metabolite, N,N-diethyl-7-formamido-4-methyl-6-oxo-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carboxamide (FOMBK), which is an opened indolic ring compound. Hydrolysis of FOMBK led to the deformylated compound 7-amino-N,N-diethyl-4-methyl-6-oxo-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carboxamide. The reactions of LSD with the peroxidases were chemiluminescent and sensitive to inhibition by reactive oxygen scavengers, which indicated that the classic peroxidase cycle is involved in this new alternative metabolic pathway. Considering that MPO is abundant in immune cells and also present in the central nervous system, the degradation pathway described in this study suggests a possible route of LSD metabolism that may occur concurrently with the in vivo reaction catalyzed by the cytochrome P450 system.

Keywords

Horseradish peroxidase Indole compounds Lysergic acid diethylamide LSD metabolism Myeloperoxidase Neutrophils Leukocytes 

Abbreviations

AFMK

N-Acetyl-N-formyl-5-methoxykynuramine

AOMBK

7-Amino-N,N-diethyl-4-methyl-6-oxo-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carboxamide

CID

Collision induced dissociation

CNS

Central nervous system

DPI

Diphenyliodonium

ESI

Electrospray ionization

FOMBK

N,N-Diethyl-7-formamido-4-methyl-6-oxo-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carboxamide

H2O2

Hydrogen peroxide

HRP

Horseradish peroxidase

KYN

Kynurenine

LC-UV–ESI–MS

Liquid chromatography-UV detection–electrospray ionization–mass spectrometry

LSD

Lysergic acid diethylamide

MPO

Myeloperoxidase

m/z

Mass-to-charge ratio

nor-LSD

N-Desmethyl-LSD

O2

Superoxide anion

O-H-LSD

2-Oxo-3-hydroxy-LSD

PMA

Phorbol 12-myristate 13-acetate

ROS

Reactive oxygen species

SOD

Superoxide dismutase

TOF

Time-of-flight

Notes

Acknowledgments

The authors thanks the Sao Paulo Research Foundation (FAPESP, Sao Paulo) and the National Counsel of Technological and Scientific Development (CNPq, Brasília).

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Copyright information

© Japanese Association of Forensic Toxicology and Springer 2012

Authors and Affiliations

  • Melissa M. Gomes
    • 1
  • Felipe A. Dörr
    • 1
  • Luiz H. Catalani
    • 2
  • Ana Campa
    • 1
  1. 1.Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical SciencesUniversity of São PauloSão PauloBrazil
  2. 2.Department of Fundamental Chemistry, Chemistry InstituteUniversity of São PauloSão PauloBrazil

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