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Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update

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Abstract

Trichothecenes are a large family of structurally related toxins mainly produced by Fusarium genus. Among the trichothecenes, T-2 toxin and deoxynivalenol (DON) cause the most concern due to their wide distribution and highly toxic nature. Trichothecenes are known for their inhibitory effect on eukaryotic protein synthesis, and oxidative stress is one of their most important underlying toxic mechanisms. They are able to generate free radicals, including reactive oxygen species, which induce lipid peroxidation leading to changes in membrane integrity, cellular redox signaling, and in the antioxidant status of the cells. The mitogen-activated protein kinases signaling pathway is induced by oxidative stress, which also induces caspase-mediated cellular apoptosis pathways. Several new metabolites and novel metabolic pathways of T-2 toxin have been discovered very recently. In human cell lines, HT-2 and neosolaniol (NEO) are the major metabolites of T-2 toxin. Hydroxylation on C-7 and C-9 are two novel metabolic pathways of T-2 toxin in rats. The metabolizing enzymes CYP3A22, CYP3A29, and CYP3A46 in pigs, as well as the enzymes CYP1A5 and CYP3A37 in chickens, are able to catalyze T-2 toxin and HT-2 toxin to form the C-3′–OH metabolites. Similarly to carboxylesterase, CYP3A29 possesses the hydrolytic ability in pigs to convert T-2 toxin to NEO. T-2 toxin is able to down- or upregulate cytochrome P-450 enzymes in different species. The metabolism of DON in humans is region-dependent. Free DON and DON-glucuronide are considered to be the biomarkers for humans. The masked mycotoxin DON-3-β-d-glucoside can be hydrolyzed to free DON in the body. This review will provide useful information on the progress of oxidative stress as well as on the metabolism and the metabolizing enzymes of T-2 toxin and DON. Moreover, the literature will throw light on the blind spots of metabolism and toxicological studies in trichothecenes that have to be explored in the future.

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Abbreviations

ALAT:

Alanine aminotransferase

ALT:

Alanine transaminase

ASAT:

Aspartate aminotransferase

AST:

Aspartate transaminase

ATA:

Alimentary toxic aleukia

BBB:

Blood–brain barrier

CAT:

Catalase

CES1C5:

Carboxylesterase 1C5

CYP450:

Cytochrome P-450

DOM-1:

C12,13-deepoxy-DON

DON:

Deoxynivalenol

DON-3-Glc:

DON-3-O-glucoside

DON-GlcA:

DON-glucuronide

EPHX1:

Epoxide hydrolase

EROD:

Ethoxyresorufin O-deethylase

GGT:

γ-Glutamyltransferase

GPT:

Glutamate pyruvate transaminase

GPx:

Glutathione peroxidase

GSH:

Glutathione

HSP-70:

Heat-shock protein-70

MAPK:

Mitogen-activated protein kinases

MDA:

Malondialdehyde

MROD:

Methoxyresorufin O-demethylase

NEO:

Neosolaniol

NHA:

Normal human astrocytes

NHLF:

Normal human lung fibroblasts

NMR:

Nuclear magnetic resonance

PBMC:

Peripheral blood mononuclear cells

PROD:

Pentoxyresorufin O-depentylase

ROS:

Reactive oxygen species

RPTEC:

Renal proximal tubule epithelial cells

SOD:

Superoxidae dismutase

TBARS:

Thiobarbituric acid substance

TDI:

Tolerable daily intake

UDPGA:

Uridine 5′-diphospho-glucuronic acid

UGTs:

UDP-glucuronosyltransferases

γ-GT:

γ-Glutamyl transferase

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Acknowledgments

This work was financially supported by National Basic Research Program of China (973 program; Grant no.2009CB118800) and the project of Excellence FIM UHK as well as the long-term development plan UHHK.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. College of Life Science, Yangtze University, Jingzhou, 434025, Hubei, People’s Republic of China

    Qing-Hua Wu

  2. National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, MOA Laboratory of Risk Assessment for Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, 430070, Hubei, People’s Republic of China

    Xu Wang & Zong-Hui Yuan

  3. Department of Traumatology, BG Trauma Center, University of Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany

    Wei Yang & Andreas K. Nüssler

  4. Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center, University of Heidelberg, Ludwigshafen, Germany

    Ling-Yun Xiong

  5. Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic

    Qing-Hua Wu & Kamil Kuča

  6. Biomedical research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic

    Kamil Kuča

  7. Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic

    Vlastimil Dohnal

  8. College of Horticulture and Garden, Yangtze University, Jingzhou, 434023, Hubei, People’s Republic of China

    Xiu-Juan Zhang

Authors
  1. Qing-Hua Wu
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  2. Xu Wang
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  3. Wei Yang
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  4. Andreas K. Nüssler
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  5. Ling-Yun Xiong
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  6. Kamil Kuča
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  7. Vlastimil Dohnal
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  8. Xiu-Juan Zhang
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  9. Zong-Hui Yuan
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Corresponding authors

Correspondence to Qing-Hua Wu or Zong-Hui Yuan.

Additional information

Qing-Hua Wu, Xu Wang, and Wei Yang have contributed equally to this work.

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Wu, QH., Wang, X., Yang, W. et al. Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update. Arch Toxicol 88, 1309–1326 (2014). https://doi.org/10.1007/s00204-014-1280-0

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  • DOI: https://doi.org/10.1007/s00204-014-1280-0

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