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

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.

Genotoxic Effects of Mycotoxins: Review

“…21,107,108 Trikotesenlerin mitokondriyal fonksiyonları etkilediği, lipit peroksidasyonunu değiştirdiği, membran stabilitesini bozduğu ve hücre ölümünü uyardığı gösterilmiştir. 109,110 A grubu trikotesen ailesine ait T-2 toksini diğer trikosenlere göre tahıllarda kirletici olarak daha az bulunmasına rağmen, trikotesenler arasında en yüksek toksisiteye sahip olması nedeni ile dikkat çekmektedir. 69 Toksisitede T-2 toksininin asıl hedefi immün sistemdir.…”

Fumonisins: oxidative stress-mediated toxicity and metabolism in vivo and in vitro

“…The MAPK superfamily of serine/threonine kinases is activated by a number of extracellular stimuli and is involved in signal transduction cascades that play an important regulatory role in cell apoptosis (Matsuzawa and Ichijo 2005). Three major mammalian MAPKs were extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (Wang et al 2012;Wu et al 2014). The expression of Hsp25/27 and Hsp70 might affect cell survival by interfering with apoptotic machinery and inhibiting apoptosis both upstream and downstream of the caspase cascade in a caspase-independent manner.…”

Low-molecular-weight metabolite systems chemistry

“…Among the most prominent and deleterious of them we find trichothecene sesquiterpenes. An often mentioned compound is deoxynivaleol (DON, 4.20), which affects the functioning of ribosomes (ribotoxic stress response) and can cause oxidative stress (Wu et al, 2014). Monoterpenes, in addition to phenylpropenes, represent the major plant odor components; derivatives such as myrcene (4.21) occur in especially large amounts in conifer resin.…”