The toxicity of microcystin-LR in swine and mice

Abstract

Microcystin-LR (MCLR) is a monocyclic heptapeptide hepatotoxin produced by the cyanobacterium Microcystis aeruginosa. One gilt given whole M. aeruginosa cells ig containing 0.3% MCLR and des-methyl MCLR at 2.1 g/kg had severe panlobular hepatic necrosis and hemorrhage when euthanatized at 32.5 hr postdosing.

Mean liver and kidney weights increased 50-64% and 20-32%, respectively, in two strains of male mice that died within 200 minutes after a single lethal ip dose of purified MCLR. Mice that survived an ip LD$\sb{23}$ or LD$\sb{30}$ of MCLR had significantly longer survival times and higher survival rates when given an approximate ip LD$\sb{100}$ minimum (40-75 $\mu$g/kg) 2 or 3 days later.

The liver (34.01 IU/g), pancreas (5.43 IU/g), and kidney (3.24 IU/g) were the only swine tissues with mean arginase activity (ARG) greater than 0.52 IU/g. The serum t${1\over2}$ of ARG in a barrow and gilt were 85.8 and 128.0 minutes (min).

Between 12 and 24 min after anesthetized gilts were given a lethal iv dose of purified MCLR (72 $\mu$g/kg), mean aortic and central venous pressures, and renal and hepatic perfusion decreased ($\downarrow$) significantly, while portal venous pressure increased ($\uparrow$) significantly. Significant changes at 45 min included $\uparrow$ bile acids, total bilirubin, lactate, K, and pO$\sb2$, and $\downarrow$ platelet count, base excess, Hct, HCO$\sb3-$, and pCO$\sb2$. At 90 min, significant changes included $\uparrow$ ARG, P, BUN, and creatinine, and $\downarrow$ pH and glucose. Significant changes 150 min postdosing included $\uparrow$ AST, AP, ALT, CPK, and LDH. Livers were markedly enlarged, dark purple-red in color, and readily exuded blood on cut surfaces. Significantly $\uparrow$ liver weights and liver Fe and Hb concentrations were suggestive that 37.9% of the estimated blood volume was present in the liver. The major cause of acute death ($<$5 hr) following iv MCLR dosing in swine is hypovolemic shock which results from massive intrahepatic hemorrhage.