Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation

Ma, Liang; Zhao, Hengqiang; Xia, Qingsu; Cai, Lining; Fu, Peter P.

doi:10.1016/j.jfda.2015.06.001

Title: Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation

Journal Article · Tue Sep 01 00:00:00 EDT 2015 · Journal of Food and Drug Analysis

DOI:https://doi.org/10.1016/j.jfda.2015.06.001· OSTI ID:1250565

Ma, Liang; Zhao, Hengqiang; Xia, Qingsu; Cai, Lining; Fu, Peter P.

Pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic in experimental animals. Because of their widespread distribution in the world, PA-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Upon metabolism, PAs generate reactive dehydro-PAs and other pyrrolic metabolites that lead to toxicity. Dehydro-PAs are known to react with glutathione (GSH) to form 7-GSH-(+/–)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (7-GS-DHP) in vivo and in vitro and 7,9-diGS-DHP in vitro. To date, the phototoxicity of GS-DHP adducts has not been well studied. In this study, we synthesized 7-GS-DHP, a tentatively assigned 9-GS-DHP, and two enantiomeric 7,9-diGS-DHP adducts by reaction of dehydromonocrotaline with GSH. The two 7,9-diGS-DHPs were separated by high performance liquid chromatography (HPLC) and their structures were characterized by ¹H nuclear magnetic resonance (NMR) and ¹H–¹H correlation spectroscopy (COSY) NMR spectral analysis. Photoirradiation of 7-GS-DHP, 9-GS-DHP, and the two 7,9-diGS-DHPs as well as dehydromonocrotaline, dehydroheliotrine, and the 7-R enantiomer of DHP (DHR), by UVA light at 0 J/cm², 14 J/cm², and 35 J/cm² in the presence of a lipid, methyl linoleate, all resulted in lipid peroxidation in a light dose-responsive manner. The levels of lipid peroxidation induced by the two isomeric 7,9-diGS-DHPs were significantly higher than that by 7-GS-DHP and 9-GS-DHP. When 7,9-diGS-DHP was irradiated in the presence of sodium azide (NaN₃), the level of lipid peroxidation decreased; lipid peroxidation was enhanced when methanol was replaced by deuterated methanol. These results suggest that singlet oxygen is a product induced by the irradiation of 7,9-diGS-DHP. When irradiated in the presence of superoxide dismutase (SOD), the level of lipid peroxidation decreased, indicating that lipid peroxidation is also mediated by superoxide. These results indicate that lipid peroxidation is mediated by reactive oxygen species (ROS). These results suggest that 7,9-diGS-DHPs are phototoxic, generating lipid peroxidation mediated by ROS.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC); U.S. Food and Drug Administration (FDA)

Grant/Contract Number:: SC0014664

OSTI ID:: 1250565

Alternate ID(s):: OSTI ID: 1904996

Journal Information:: Journal of Food and Drug Analysis, Journal Name: Journal of Food and Drug Analysis Vol. 23 Journal Issue: 3; ISSN 1021-9498

Publisher:: The Journal of Food and Drug Analysis (JFDA), Food and Drug Administration, Taiwan (TFDA)Copyright Statement

Country of Publication:: Taiwan, Province of China

Language:: English

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Cited by: 19 works

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9-diGS-DHP adducts
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Title: Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation

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