Oxidative metabolism by P450 and function coupling to efflux systems: Modulation of mycotoxin toxicity

Abstract

Man is permanently exposed to exogenous substances, either natural ones (e.g. mycotoxins, plant extracts) or man–made compounds such as pesticides or drugs. In some cases, such foreign compounds can exert either therapeutic (drugs) or toxic effects, or both. In particular, fungi are the source of a number of different secondary metabolites having such therapeutic or toxic effects. The efficiency or toxicity of foreign compounds depends on their ability to cross the cytoplasmic membrane. The exogenous molecules subsequently bind to their specific receptor in the cytoplasm or nucleus of the cell, but they are also attacked by the detoxification proteins, which in mammals are mainly composed of two types of membrane enzyme systems: cytochrome P450s, which functionalize hydrophobic xenobiotics, and an active P–glycoprotein (P–gp) transport system involved in the efflux of xenobiotics. These processes are illustrated through the use of two fungal cyclopeptides, cyclosporin A (CsA) and roquefortine C. The former, CsA, is known to be an immunosuppressor, while the latter, roquefortine C, is a potentially neurotoxic compound. CsA inhibits P–gp in a different way from its metabolites, whereas roquefortine C activates P–gp and also inhibits P450–3A and other haemoproteins. The current observations show that the two detoxification systems complement each other, resulting in a given toxicity level. The two mammal enzyme systems might therefore prove useful in the development of toxicity screening procedures.

Keywords:

• Mycocotoxins
• cyclosporin A
• roquefortine C
• cytochrome P450
• P–glycoprotein

Acknowledgements

The authors thank Dr A. Mabondzo for neuroblastoma tests and Dr S. Orlowski (both CEA, Saclay, France) for P-gp assays, Dr C. Gaspard (CNRS, ICSN, Gif sur Yvette, France) for cytotoxicity tests. The authors also thank Dr A. Green for helpful comments and proofreading. Part of this work was supported by the AC 009E Environment et Santé program of the French Ministère de l’Aménagement du Territoire et de l’Environment.