Biomedical Mechanics of Trichothecene Mycotoxins

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Trichothecene mycotoxins are cytotoxic that inhibit protein synthesis in a

variety of eukaryotic cells in humans, other mammals, birds, fish, and a variety

of invertebrates and plants. Beginning 5 minutes after exposure to T-2 toxins,

inhibition of protein synthesis in cells is observed. Researchers have found

that trichothecene mycotoxins act by inhibiting either the initiation or the

elongation process of translation by interfering with peptidyl transferase.

Scheduled DNA synthesis is also strongly inhibited in cells that are exposed to

trichothecene mycotoxins, although to a lesser degree than in protein synthesis.

 

Trichothecene also stimulates lipid peroxidation that induces alterations in the

cell membrane. Once the toxin crosses the plasma membrane barrier, they enter

the cell, where they can interact with a number of targets, including ribosomes

and mitochondria. The toxins then inhibit electron transport activity and

contribute to cellular cytotoxicity.

 

Trichothecene mycotoxins do not appear to require metabolic activation to exert

their biological activity. The rapidity with which trichothecene mycotoxins acts

means they have the molecular capability to directly react with cellular

components. The toxins rapidly cross the pulmonary and intestinal mucosa and

enter the systemic circulation to induce the toxin-related toxicoses. Entry by

way of the skin is slowly absorbed especially when applied as dust or powder.

The Pharmacokinetics of the trichothecene mycotoxins are functions of the rate

of absorption into the general circulation, metabolism, tissue distribution, and

excertion. The liver is the major organ of metabolism.

 

A microsomal, nonspecific carboxylesterase from liver selectively hydrolyses the

C-4 acetyl group of T-2 toxin to yield HT-2 toxin. In addition to hepatic

microsomes, the trichothecene specific carboxylesterase activity has been

detected in brain, kidney, spleen, intestine, white blood cells, and

erythrocytes. This emphasizes the importance of carboxylesterase in detoxifying

the trichothecene mycotoxins. When oxygen is removed from the epoxide group of a

trichothecene mycotoxin to yield the carbon-carbon bond, deepoxy metabolites are

formed. The deepoxy metabolites are essentially nontoxic. This observation

indicates that epoxide reduction is a single-step detoxification reaction for

trichothecene mycotoxins.

 

The formation of glucuronide conjugates generally results in the elimination of

toxicological activity of xenobiotics, which in certain species could represent

a major route of detoxification of trichothecene mycotoxins.

 

http://www.globalsecurity.org/wmd/intro/bio_trichothecene-mechs.htm