VPT 421: Veterinary Toxicology (2+0)

Mechanisms of Action

MECHANISM OF ACTION

• Fumonisin B1 apparently causes its toxic effects, at least in part, by inhibiting the action of sphingosine N-acyltransferase, an enzyme involved in the conversion of sphinganine and sphingosine into sphingolipids.
• Sphingosine is an important second messenger in a range of cell types.
• Sphinganine can be very cytotoxic or can lead to cell proliferation and affect a wide variety of cellular systems.
• Inhibition of N-acyltransferase may cause increase in sphinganine concentration in tissues.
• Sphingolipids are important in regulation of cell growth, differentiation, and neoplastic transformation.
• Alteration in sphingolipid concentrations and functions, especially in the vasculature, also are believed to contribute to the major signs and lesions of fumonisin toxicosis.
• In swine, fumonisin causes damage to hepatocyte membranes causing release of membrane fragments to circulation. These are trapped in the lung where they are engulfed by pulmonary intravascular macrophages which may release substances that activate neutrophils and alter capillary permeability resulting in pulmonary edema.
• Cardiac failure and pulmonary hypertension, due to pulmonary vasoconstriction, may also occur in swine, predisposing them to pulmonary edema.