Are Reactive Oxygen Species Involved in Microcystin-LR Intoxication?

The toxic cyclic heptapeptide, microcystin-LR (cyanoginosin-LR, microcystin-A), isolated from the cyanobacterium Microcystis aeruginosa, kills mice within 1 hr after i.v. or i.p. exposure to an acute lethal dose. Hepatic engorgement and thrombocytopenia develop 30-40 min postchallenge. Histologic findings after death include severe hemorrhagic liver necrosis, renal nephrosis, and microscopic pulmonary thrombi. The hepatic lesion is in the centrilobular region, where drug metabolizing enzymes are present in highest concentrations, suggesting pathologic changes might be mediated by a microcystin metabolite rather than directly by the toxin. Free radical formation occurs during the metabolism of several hepatotoxins that cause similar lesions, therefore, we hypothesized that compounds that alter the concentration of reactive oxygen species would also alter the toxic effects of microcystin. We show here that pretreatment with a free radical generator, alloxan; a free radical scavanger, butylated hydroxyanisole; or an iron chelator/inhibitor of lipid peroxidation, desferrioxamine, did not alter the severity of microcystin-LR intoxication in fed mice. Furthermore, mice for 24 hr before testing, which unmasks lipid peroxidation in paracetamol intoxication, did not alter the effect of BHA pretreatment. Keywords: Antidotes, Pathology.