Mycotoxins: Mechanisms of action at the molecular level

Mycotoxins comprise a group of chemically diverse compounds exerting a broad variety of biochemical effects.. In the evaluation of the possible role of mycotoxins in human diseases, molecular mechanisms involved in chemically induced carcinogenesis are of particular interest. Metabolism mediated toxicity was first described for aflatoxin B1 and the species-specific balance between CYP450-dependent activation and the further processing of the electrophilic metabolites have been used to correlate experimental data to epidemiological investigations. Recent technologies in molecular biology allow the detailed description of human isoenzymes involved in biotransformation processes and also the characterization of the mutations initiating tumour development. A parallel approach has been applied to identify the role of biotransformation processes in the etiology of ochratoxin A related pathologies. As ochratoxin A is a typical nephrotoxin, renal-specific biotransformation processes seem to be involved in the target organ toxicity. In contrast to aflatoxin B1 and ochratoxin A, fumonisins exert their toxicity by a completely different mechanism. Fumonisin B1 has been found to disrupt sphingolipid biosynthesis both in vivo and in vitro, resulting in an accumulation of free sphinganine. This effect has been observed in all target tissues including liver, kidneys and the central nervous system and is considered to be the primary event in the species-specific pathologies related to dietary fumonisin exposure. Furthermore, there is accumulating evidence that this mechanism is involved in the tumour promoting activity of fumonisins as well. These findings imply, that fumonisins exert not only a unique effect in relation to other mutagenic and carcinogenic mycotoxins but also in comparison to other neurotoxic mycotoxins.