Author
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Riley, Ronald |
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Voss, Kenneth |
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PESTKA, JAMES - MSU, ELANSING, MI |
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Submitted to: Meeting Abstract
Publication Type: Abstract Only Publication Acceptance Date: 10/15/2006 Publication Date: 11/1/2006 Citation: Riley, R.T. , Voss, K.A. and Pestka, J. Mode of action of mycotoxins. Proceedings of The World Mycotoxin Forum, the Fourth Conference, November 6-8, 2006. Alltech Corpmedia, DVD M829 NTSC Disk 3: Research, Released March 26, 2007. (Instructional DVD). Cincinnatti, OH. Interpretive Summary: Abstract - no summary needed. Technical Abstract: Mycotoxins are a structurally disparate group of toxic chemicals. There only common link is that they are all produced by fungi. It is therefore not surprising that their biochemical mechanisms of action are as diverse as their taxonomic origins. The study of biochemical and cellular mechanisms of toxicity is founded on the fact that the action of a toxic chemical is distinct from its effects. Mechanism of action is not a precisely defined concept. The easiest way to envision mechanism of action is as a series of events initiated by an interaction between a specific toxic chemical and some biochemical entity (the proximate cause) and from which there occurs secondary events at the subcellular and cellular level that cascade into a complex array of additional downstream events leading ultimately to observable effects at the organismal level. Secondary effects are often misidentified as the proximate cause (initiating event). For the more toxic mycotoxins, the ultimate observable effect is often cell death; however, adverse physiological effects, which can be expressed as normal cellular responses but at inappropriate times, are also common. The simplest mechanism of action is when a toxic chemical mimics a physiologically relevant agonist (first messenger) for a classical receptor. This can occur by binding to a specific receptor and either initiating or inhibiting the normal function of the receptor-mediated response. For mycotoxins, this is most easily seen with zearalenone which is known to bind to cytosolic estrogen receptors and initiate the estrogenic response in target tissues. Unfortunately, most of the mechanisms of action are not as simple as those that involve specific binding to classical receptors and the observed effects are also not easily connected to the initial biochemical action (the proximate cause). For example, patulin binds with high affinity to protein- and non-protein-sulfhydryls. The downstream effects can range from inhibition of membrane transporters to lipid peroxidation depending on the proteins/peptides that are most affected. Other mycotoxins such as the fumonisins, cyclopiazonic acid and ochratoxin mimic substrates for specific enzymes/proteins and thus interfere with specific protein functions. The ultimate downstream effects are difficult to predict and are often influenced by subtle differences that are cell or tissue specific and can be modulated by other environmental and physiological factors. For example, cyclopiazonic acid is a specific inhibitor of the sarcoplasmic and endoplasmic reticulum calcium transport ATPase (SERCA). The consequences of inhibition of calcium transport in muscle are quite different than the effects of cyclopiazonic acid in epithelial cells. Likewise, fumonisins inhibit de novo sphingolipid metabolism resulting in changes in several sphingolipid intermediates that are ligands for receptors in signaling pathways that control both cell death and cell survival. Examples of environmental factors that can modulate the downstream response to fumonisin inhibition of ceramide synthase include folate sufficiency and antioxidant status. Another example of specific binding is deoxynivalenol (DON) (and other trichothecenes) which binds to the eukaryotic ribosome (28s rRNA) and, thus, inhibits translation of mRNA into protein and initiates the ribotoxic stress response in affected cells. The observed toxic effects of DON inhibition of protein synthesis will be quite different in tissues comprised of quiescent cells compared to tissues in which cells are rapidly proliferating. Finally, some mycotoxins must be metabolized in order to be highly toxic. For example, aflatoxin B1 (AFB1) when metabolized to its epoxide readily reacts with DNA and if metabolized to the dihydrodiol reacts readily with proteins. Thus, the ability of the tissue to metabolize AFB1 is |
