Human CYP3A4-mediated toxification of the pyrrolizidine alkaloid lasiocarpine

Ebmeyer, Johanna; Braeuning, Albert; Glatt, Hansruedi; These, Anja; Hessel-Pras, Stefanie; Lampen, Alfonso

doi:10.1016/j.fct.2019.05.019

Cited by 36 publications

(31 citation statements)

References 52 publications

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“…Although much research has focused on the identification of PA metabolites (Buhler and Kedzierski 1986 ; Fashe et al 2014 , 2015 ; Fu et al 2004a ), their quantification revealed that a large portion is still unknown. Furthermore, GSH-DHP conjugates like 7,9-diglutathionyl-6,7-dihydro-1-hydroymethyl-5H-pyrrolizidine (diGSH-DHP), and 9-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizidine (monoGSH-DHP) suggested as biomarkers for in vitro metabolic activation were not detectable when CYP content is low—for instance when using S9 as metabolic system instead of microsomes, or were only detectable after long-term incubation (Ebmeyer et al 2019 ; Geburek et al 2020 ; Kolrep et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

In vitro biotransformation of pyrrolizidine alkaloids in different species: part II—identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids

2020

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Pyrrolizidine alkaloids (PA) exert their toxic effects only after bioactivation. Although their toxicity has already been studied and metabolic pathways including important metabolites were described, the quantification of the latter revealed a large unknown portion of the metabolized PA. In this study, the qualitative and quantitative metabolite profiles of structurally different PAs in rat and human liver microsomes were investigated. Between five metabolites for europine and up to 48 metabolites for lasiocarpine were detected. Proposals for the chemical structure of each metabolite were derived based on fragmentation patterns using high-resolution mass spectrometry. The metabolite profiles of the diester PAs showed a relatively good agreement between both species. The metabolic reactions were summarized into three groups: dehydrogenation, oxygenation, and shortening of necic acid(s). While dehydrogenation of the necine base is considered as bioactivation, both other routes are considered as detoxification steps. The most abundant changes found for open chained diesters were dealkylations, while the major metabolic pathway for cyclic diesters was oxygenation especially at the nitrogen atom. In addition, all diester PAs formed several dehydrogenation products, via the insertion of a second double bond in the necine base, including the formation of glutathione conjugates. In rat liver microsomes, all investigated PAs formed dehydropyrrolizidine metabolites with the highest amount formed by lasiocarpine, whereas in human liver microsomes, these metabolites could only be detected for diesters. Our findings demonstrate that an extensive analysis of PA metabolism can provide the basis for a better understanding of PA toxicity and support future risk assessment.

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Section: Introductionmentioning

confidence: 99%

In vitro biotransformation of pyrrolizidine alkaloids in different species: part II—identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids

2020

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“…When ingested, PAs with an unsaturated bond in 1,2 position of the necine unit ( Fig. 1) (hereafter called unsaturated PAs) metabolically oxidize and react with proteins and nucleic acids [43][44][45][46] resulting in hepatotoxic, mutagenic and carcinogenic effects 16,37,41,[46][47][48][49][50] .…”

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confidence: 99%

“…Plants with high concentrations of unsaturated PAs are responsible for the death of cattle 18,55 . Toxic effects in humans such as hepatic sinusoidal obstruction syndrome and incidents of acute and subacute food poisoning with high morbidity and mortality have been reported from many countries 24,25,37,38,44,45,50,55,56 . The World Health Organization (WHO) recommends minimizing PA exposure to humans as much as possible 57 .…”

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The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids

Kisielius

Hama

Skrbic

et al. 2020

Sci Rep

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Pyrrolizidine alkaloids (PAs) are persistent mutagenic and carcinogenic compounds produced by many common plant species. Health authorities recommend minimising human exposure via food and medicinal products to ensure consumer health and safety. However, there is little awareness that PAs can contaminate water resources. Therefore, no regulations exist to limit PAs in drinking water. This study measured a PA base concentration of ~ 70 ng/L in stream water adjacent to an invasive PA-producing plant Petasites hybridus (Asteraceae). After intense rain the PA concentration increased tenfold. In addition, PAs measured up to 230 ng/L in seepage water from groundwater wells. The dominant PAs in both water types corresponded to the most abundant PAs in the plants (senkirkine, senecionine, senecionine N-oxide). The study presents the first discovery of persistent plant toxins in well water and their associated risks. In addition, it for the first time reports monocrotaline and monocrotaline N-oxide in Petasites sp.

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“…The C-oxidation pathway is generally considered as the metabolic activation, which catalyzes the dehydrogenation of PAs to DHPAs (Mattocks and Jukes 1990). CYP3A and CYP2B subfamilies are responsible for the metabolic activation of toxic PAs in experimental animals Huan et al 1998a), while CYP3A4 isozyme predominately catalyzes the PA bioactivation in humans (Chung and Buhler 1994;Dueker et al 1992a;Ebmeyer et al 2019;Lin et al 2000;Miranda et al 1991;Williams et al 1989a). Using human liver microsomes and recombinant CYPs, Ruan et al investigated metabolic activation of different PAs and demonstrated that CYP1A1, CYP1A2, CYP2A6, CYP3A4, CYP3A5, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were responsible for the metabolic activation of retronecine/heliotridinetype PAs, while CYP3A4 and CYP3A5 predominantly mediated the metabolic activation of otonecine-type PAs (Ruan et al 2014b).…”

Section: Cytochrome P450 Enzymesmentioning

confidence: 99%

Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids

Zhu

et al. 2021

Arch Toxicol

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Pyrrolizidine alkaloids (PAs) and PA N-oxides are common phytotoxins produced by over 6000 plant species. Humans are frequently exposed to PAs via ingestion of PA-containing herbal products or PA-contaminated foods. PAs require metabolic activation to form pyrrole-protein adducts and pyrrole-DNA adducts which lead to cytotoxicity and genotoxicity. Individual PAs differ in their metabolic activation patterns, which may cause significant difference in toxic potency of different PAs. This review discusses the current knowledge and recent advances of metabolic pathways of different PAs, especially the metabolic activation and metabolism-mediated cytotoxicity and genotoxicity, and the risk evaluation methods of PA exposure. In addition, this review provides perspectives of precision toxicity assessment strategies and biomarker development for the risk control and translational investigations of human intoxication by PAs.

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Human CYP3A4-mediated toxification of the pyrrolizidine alkaloid lasiocarpine

Cited by 36 publications

References 52 publications

In vitro biotransformation of pyrrolizidine alkaloids in different species: part II—identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids

In vitro biotransformation of pyrrolizidine alkaloids in different species: part II—identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids

The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids

Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids

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