Fasting Augments Pyrrolizidine Alkaloid-induced Hepatotoxicity

Overview

Journal Arch Toxicol

Specialty Toxicology

Date 2021 Nov 18

PMID 34792613

Citations 5

Authors

Jiang Ma

Chunyuan Zhang

Yisheng He

Xinmeng Chen

Ge Lin

Affiliations

Soon will be listed here.

Abstract

Pyrrolizidine alkaloids (PAs) are phytotoxins widely present in various natural products and foodstuffs. The present study aims to investigate the effects of fasting on PA-induced hepatotoxicity and the underlying biochemical mechanisms. The results of hepatotoxic study showed that 15-h overnight fasting significantly exacerbated the hepatotoxicity of retrorsine (RTS, a representative toxic PA) in fasted rats compared to fed rats, as indicated by remarkably elevated plasma ALT and bilirubin levels and obvious liver histological changes. Further toxicokinetic studies revealed that fasting significantly enhanced cytochromes P450 enzymes (CYPs)-mediated metabolic activation of RTS leading to increased formation of pyrrole-protein adducts and thus decreased the in vivo exposure and excretion of both parent RTS and its N-oxide metabolite. Metabolic studies demonstrated that fasting induced enzyme activities of CYP1A2, CYP2B6 and CYP2E1 that participated in catalyzing RTS to its reactive pyrrolic metabolites. Moreover, fasting also dramatically decreased hepatic glutathione (GSH) content, which restricted the detoxification of GSH by neutralizing the reactive pyrrolic metabolite of RTS, further contributing to the enhanced hepatotoxicity. The present findings may have an impact on future PA toxicity tests with different dietary styles and/or risk assessment of metabolite-mediated toxins by considering the profound effects of fasting.

Citing Articles

Human liver progenitor-like cells-derived extracellular vesicles promote liver regeneration during acute liver failure.

Chen Y, Wu Y, Sun H, Zhang H, Tang D, Yuan T Cell Biol Toxicol. 2024; 40(1):106.

PMID: 39604571 PMC: 11602810. DOI: 10.1007/s10565-024-09954-6.

In vitro-in silico study on the influence of dose, fraction bioactivated and endpoint used on the relative potency value of pyrrolizidine alkaloid N-oxides compared to parent pyrrolizidine alkaloids.

Alhejji Y, Widjaja F, Tian S, Hoekstra T, Wesseling S, Rietjens I Curr Res Toxicol. 2024; 6:100160.

PMID: 38469320 PMC: 10926302. DOI: 10.1016/j.crtox.2024.100160.

Effects of Cadmium on Kidney Function of the Freshwater Turtles Mauremys reevesii.

Dong A, Dong H, He H, Dong A, Yan J, Huo J Biol Trace Elem Res. 2022; 201(6):3000-3005.

PMID: 35986187 DOI: 10.1007/s12011-022-03397-y.

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway.

Liu Y, Xue N, Zhang B, Lv H, Li S Biomolecules. 2022; 12(7).

PMID: 35883482 PMC: 9312970. DOI: 10.3390/biom12070927.

Fasting Enhances the Acute Toxicity of Acrylonitrile in Mice via Induction of CYP2E1.

Wang S, Xing G, Li F, Yang B, Zhang Y, Aschner M Toxics. 2022; 10(6).

PMID: 35736945 PMC: 9228628. DOI: 10.3390/toxics10060337.

References

Baillie T, Rettie A . Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism. Drug Metab Pharmacokinet. 2010; 26(1):15-29. PMC: 4675351. DOI: 10.2133/dmpk.dmpk-10-rv-089. View

Brown B, Allis J, Simmons J, House D . Fasting for less than 24 h induces cytochrome P450 2E1 and 2B1/2 activities in rats. Toxicol Lett. 1995; 81(1):39-44. DOI: 10.1016/0378-4274(95)03407-2. View

Chauvin P, Dillon J, Moren A . [An outbreak of Heliotrope food poisoning, Tadjikistan, November 1992-March 1993]. Sante. 1994; 4(4):263-8. View

Chojkier M . Hepatic sinusoidal-obstruction syndrome: toxicity of pyrrolizidine alkaloids. J Hepatol. 2003; 39(3):437-46. DOI: 10.1016/s0168-8278(03)00231-9. View

Dusemund B, Nowak N, Sommerfeld C, Lindtner O, Schafer B, Lampen A . Risk assessment of pyrrolizidine alkaloids in food of plant and animal origin. Food Chem Toxicol. 2018; 115:63-72. DOI: 10.1016/j.fct.2018.03.005. View

Ebmeyer J, Rasinger J, Hengstler J, Schaudien D, Creutzenberg O, Lampen A . Hepatotoxic pyrrolizidine alkaloids induce DNA damage response in rat liver in a 28-day feeding study. Arch Toxicol. 2020; 94(5):1739-1751. PMC: 7261731. DOI: 10.1007/s00204-020-02779-2. View

Edgar J, Molyneux R, Colegate S . Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease. Chem Res Toxicol. 2014; 28(1):4-20. DOI: 10.1021/tx500403t. View

Fu P . Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation. Chem Res Toxicol. 2017; 30(1):81-93. DOI: 10.1021/acs.chemrestox.6b00297. View

Fu P, Xia Q, Lin G, Chou M . Pyrrolizidine alkaloids--genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev. 2004; 36(1):1-55. DOI: 10.1081/dmr-120028426. View

10.

He Y, Zhu L, Ma J, Lin G . Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids. Arch Toxicol. 2021; 95(6):1917-1942. DOI: 10.1007/s00204-021-03060-w. View

11.

Hessel-Pras S, Braeuning A, Guenther G, Adawy A, Enge A, Ebmeyer J . The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice. Arch Toxicol. 2019; 94(1):219-229. DOI: 10.1007/s00204-019-02582-8. View

12.

Hinson J, Pumford N, Nelson S . The role of metabolic activation in drug toxicity. Drug Metab Rev. 1994; 26(1-2):395-412. DOI: 10.3109/03602539409029805. View

13.

Kakar F, Akbarian Z, Leslie T, Mustafa M, Watson J, van Egmond H . An outbreak of hepatic veno-occlusive disease in Western afghanistan associated with exposure to wheat flour contaminated with pyrrolizidine alkaloids. J Toxicol. 2010; 2010:313280. PMC: 2905904. DOI: 10.1155/2010/313280. View

14.

Lammers L, Achterbergh R, van Schaik R, Romijn J, Mathot R . Effect of Short-Term Fasting on Systemic Cytochrome P450-Mediated Drug Metabolism in Healthy Subjects: A Randomized, Controlled, Crossover Study Using a Cocktail Approach. Clin Pharmacokinet. 2017; 56(10):1231-1244. PMC: 5591816. DOI: 10.1007/s40262-017-0515-7. View

15.

Lin G, Cui Y, Hawes E . Characterization of rat liver microsomal metabolites of clivorine, an hepatotoxic otonecine-type pyrrolizidine alkaloid. Drug Metab Dispos. 2000; 28(12):1475-83. View

16.

Lin G, Wang J, Li N, Li M, Gao H, Ji Y . Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum. J Hepatol. 2010; 54(4):666-73. DOI: 10.1016/j.jhep.2010.07.031. View

17.

Longo V, Panda S . Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab. 2016; 23(6):1048-1059. PMC: 5388543. DOI: 10.1016/j.cmet.2016.06.001. View

18.

Lu Y, Ma J, Lin G . Development of a two-layer transwell co-culture model for the in vitro investigation of pyrrolizidine alkaloid-induced hepatic sinusoidal damage. Food Chem Toxicol. 2019; 129:391-398. DOI: 10.1016/j.fct.2019.04.057. View

19.

Ma L, Zhao H, Xia Q, Cai L, Fu P . Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation. J Food Drug Anal. 2017; 23(3):577-586. PMC: 9351797. DOI: 10.1016/j.jfda.2015.06.001. View

20.

Ma J, Xia Q, Fu P, Lin G . Pyrrole-protein adducts - A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity. J Food Drug Anal. 2018; 26(3):965-972. PMC: 9303027. DOI: 10.1016/j.jfda.2018.05.005. View