7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids

He, Xiaobo; Ma, Liang; Xia, Qingsu; Fu, Peter P.

doi:10.1016/j.jfda.2016.08.001

Title: 7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids

Abstract

Plants containing pyrrolizidine alkaloids (PAs) are widespread throughout the world and are the most common poisonous plants affecting livestock, wildlife, and humans. PAs require metabolic activation to form reactive dehydropyrrolizidine alkaloids (dehydro-PAs) that are capable of alkylating cellular DNA and proteins, form (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA and DHP-protein adducts, and lead to cytotoxicity, genotoxicity, and tumorigenicity. In this study, we determined that the metabolism of riddelliine and monocrotaline by human and rat liver microsomes in the presence of N-acetylcysteine both produced 7-N-acetylcysteine-DHP (7-NAC-DHP) and DHP. Reactions of 7-NAC-DHP with 2'-deoxyguanosine (dG), 2'-deoxyadenosine (dA), and calf thymus DNA in aqueous solution followed by enzymatic hydrolysis yielded DHP-dG and/or DHP-dA adducts. These results indicate that 7-NAC-DHP is a reactive metabolite that can lead to DNA adduct formation.

Authors:: He, Xiaobo; Ma, Liang; Xia, Qingsu; Fu, Peter P.

Publication Date:: Sat Oct 01 00:00:00 EDT 2016

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

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

OSTI Identifier:: 1324014

Alternate Identifier(s):: OSTI ID: 1905023

Grant/Contract Number:: SC0014664

Resource Type:: Published Article

Journal Name:: Journal of Food and Drug Analysis

Additional Journal Information:: Journal Name: Journal of Food and Drug Analysis Journal Volume: 24 Journal Issue: 4; Journal ID: ISSN 1021-9498

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

Country of Publication:: Country unknown/Code not available

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; Food Science & Technology; Pharmacology & Pharmacy; DHP; LC-ES-MS/MS; 7-N-acetylcysteine-DHP; pyrrolizidine alkaloid

Citation Formats


                    He, Xiaobo, Ma, Liang, Xia, Qingsu, and Fu, Peter P. 7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids.  Country unknown/Code not available: N. p., 2016. 
Web.  doi:10.1016/j.jfda.2016.08.001.

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                    He, Xiaobo, Ma, Liang, Xia, Qingsu, & Fu, Peter P. 7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids.  Country unknown/Code not available.  https://doi.org/10.1016/j.jfda.2016.08.001

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                    He, Xiaobo, Ma, Liang, Xia, Qingsu, and Fu, Peter P. Sat .  
"7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids".  Country unknown/Code not available.  https://doi.org/10.1016/j.jfda.2016.08.001.

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@article{osti_1324014,

  title        = {7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids},

  author       = {He, Xiaobo and Ma, Liang and Xia, Qingsu and Fu, Peter P.},

  abstractNote = {Plants containing pyrrolizidine alkaloids (PAs) are widespread throughout the world and are the most common poisonous plants affecting livestock, wildlife, and humans. PAs require metabolic activation to form reactive dehydropyrrolizidine alkaloids (dehydro-PAs) that are capable of alkylating cellular DNA and proteins, form (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA and DHP-protein adducts, and lead to cytotoxicity, genotoxicity, and tumorigenicity. In this study, we determined that the metabolism of riddelliine and monocrotaline by human and rat liver microsomes in the presence of N-acetylcysteine both produced 7-N-acetylcysteine-DHP (7-NAC-DHP) and DHP. Reactions of 7-NAC-DHP with 2'-deoxyguanosine (dG), 2'-deoxyadenosine (dA), and calf thymus DNA in aqueous solution followed by enzymatic hydrolysis yielded DHP-dG and/or DHP-dA adducts. These results indicate that 7-NAC-DHP is a reactive metabolite that can lead to DNA adduct formation.},

  doi          = {10.1016/j.jfda.2016.08.001},

  journal      = {Journal of Food and Drug Analysis},

  number       = 4,

  volume       = 24,

  place        = {Country unknown/Code not available},

  year         = {Sat Oct 01 00:00:00 EDT 2016},

  month        = {Sat Oct 01 00:00:00 EDT 2016}

}

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Title: 7- N -Acetylcysteine-pyrrole conjugate—A potent DNA reactive metabolite of pyrrolizidine alkaloids

Abstract

Citation Formats

Metabolic Formation of DHP-Derived DNA Adducts from a Representative Otonecine Type Pyrrolizidine Alkaloid Clivorine and the Extract of Ligularia hodgsonnii Hook journal, May 2004

Human liver microsomal reduction of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid journal, March 2005

Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine journal, January 2006

Pyrrolizidine Alkaloid-Derived DNA Adducts as a Common Biological Biomarker of Pyrrolizidine Alkaloid-Induced Tumorigenicity journal, August 2013

Full Structure Assignments of Pyrrolizidine Alkaloid DNA Adducts and Mechanism of Tumor Initiation journal, August 2012

High-Performance Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry for the Detection and Quantitation of Pyrrolizidine Alkaloid-Derived DNA Adducts in Vitro and in Vivo journal, March 2010

Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation journal, September 2015

A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids journal, May 1996

Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis journal, May 2014

Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo journal, April 2005

Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease journal, December 2014

Mechanisms for Pyrrolizidine Alkaloid Activation and Detoxification book, January 1991

Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, heliotrine journal, May 2008

Hepatotoxicity and Tumorigenicity Induced by Metabolic Activation of Pyrrolizidine Alkaloids in Herbs journal, November 2011

7-Glutathione Pyrrole Adduct: A Potential DNA Reactive Metabolite of Pyrrolizidine Alkaloids journal, March 2015

Formation of DHP-derived DNA adducts in vivo from dietary supplements and Chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids journal, September 2006

Microsomal formation of a pyrrolic alcohol glutathione conjugate of the pyrrolizidine alkaloid senecionine journal, January 1992

Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives journal, June 2015

Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo journal, August 2005

Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms journal, January 2004

GENOTOXIC PYRROLIZIDINE ALKALOIDS AND PYRROLIZIDINE ALKALOID N -OXIDES—MECHANISMS LEADING TO DNA ADDUCT FORMATION AND TUMORIGENICITY journal, January 2001

Metabolic activation of retronecine and retronecine N-oxide – formation of DHP-derived DNA adducts journal, April 2008

7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids journal, September 2015

Human Liver Microsomal Metabolism and DNA Adduct Formation of the Tumorigenic Pyrrolizidine Alkaloid, Riddelliine journal, January 2003

Metabolic Formation of DHP-Derived DNA Adducts from a Representative Otonecine Type Pyrrolizidine Alkaloid Clivorine and the Extract of Ligularia hodgsonnii Hook
journal, May 2004

Human liver microsomal reduction of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid
journal, March 2005

Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine
journal, January 2006

Pyrrolizidine Alkaloid-Derived DNA Adducts as a Common Biological Biomarker of Pyrrolizidine Alkaloid-Induced Tumorigenicity
journal, August 2013

Full Structure Assignments of Pyrrolizidine Alkaloid DNA Adducts and Mechanism of Tumor Initiation
journal, August 2012

High-Performance Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry for the Detection and Quantitation of Pyrrolizidine Alkaloid-Derived DNA Adducts in Vitro and in Vivo
journal, March 2010

Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation
journal, September 2015

A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids
journal, May 1996

Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis
journal, May 2014

Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo
journal, April 2005

Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease
journal, December 2014

Mechanisms for Pyrrolizidine Alkaloid Activation and Detoxification
book, January 1991

Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, heliotrine
journal, May 2008

Hepatotoxicity and Tumorigenicity Induced by Metabolic Activation of Pyrrolizidine Alkaloids in Herbs
journal, November 2011

7-Glutathione Pyrrole Adduct: A Potential DNA Reactive Metabolite of Pyrrolizidine Alkaloids
journal, March 2015

Formation of DHP-derived DNA adducts in vivo from dietary supplements and Chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids
journal, September 2006

Microsomal formation of a pyrrolic alcohol glutathione conjugate of the pyrrolizidine alkaloid senecionine
journal, January 1992

Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives
journal, June 2015

Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo
journal, August 2005

Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms
journal, January 2004

GENOTOXIC PYRROLIZIDINE ALKALOIDS AND PYRROLIZIDINE ALKALOID N -OXIDES—MECHANISMS LEADING TO DNA ADDUCT FORMATION AND TUMORIGENICITY
journal, January 2001

Metabolic activation of retronecine and retronecine N-oxide – formation of DHP-derived DNA adducts
journal, April 2008

7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids
journal, September 2015

Human Liver Microsomal Metabolism and DNA Adduct Formation of the Tumorigenic Pyrrolizidine Alkaloid, Riddelliine
journal, January 2003