Pyrrolizidine alkaloids (PAs) are a large class of naturally occurring plant toxins with worldwide distribution. They are of significant toxicological concern to both man and livestock. Livestock are poisoned by grazing on plants containing PAs, causing livestock loss due to liver and pulmonary lesions. PAs have also been found contaminate human food sources, such as wheat, milk, honey, herbal medicines, and herbal teas, and this may potentially cause worldwide human health problems. Monocrotaline (MCT) is a PA synthesized by Crotalaria species. Many organs may be affected by exposure to MCT with the most notable lesions been found in the liver and lung. In the liver, MCT is metabolized by cytochrome P450 monooxygenases to a highly reactive pyrrole, dehydromonocrotaline (DHM) which is thought to be responsible for the toxicity of MCT in vivo. Although the toxicological effects of MCT in the liver have been known for several decades, the mechanisms of action are not clear. In this work, we evaluated the effects of the MCT and DHM on isolated rat liver mitochondria. While MCT does not present any effect over the mitochondrial respiration, its metabolite DHM causes respiration inhibition. This effect was observed only on mitochondria respiring with glutamate plus malate at a concentration range of 50-500 mmol/L. In according with this, DHM also inhibited NADH-desidrogenase activity by 100% at the concentration of 200 mmol/L and promoted collapse of membrane potential on mitochondria energized with glutamate plus malate by 50% at 250 mmol/L showing that its inhibition site, in the respiratory chain, is the complex I. At the same concentration range, it inhibited ATP synthesis by 60%. Our results shown that DHM inhibits complex I enzymatic activity of the respiratory chain interfering with mitochondrial respiration and oxidative phosphorilation, and suggest that these effects can be involved in MCT liver toxicity.

Supported by FAPESP, Capes and CNPq