Synthetic seleno-organic compound with glutathione peroxidase-like activity in the chick

The glutathione peroxidase activity catalyzed by the seleno-organic anti-inflammatory drug Ebselen (registered under the trademark of the Natterman Corp. Cologne, FRG) [PZ51, 2-phenyl-1,2-benzisoselenazol-3(2H)on], as measured by NADPH oxidation, was inhibited in vitro by the selenium-dependent glutathione peroxidase (SeGSHpx) inhibitors aurothioglucose and D-(-)penicillamine HCl. Vitamin E- and selenium-deficient chicks were given 0, 80 or 320 ppm PZ51 in diets devoid of vitamin E and supplemented with low levels of sodium selenite (0.04 ppm selenium added to the basal diet containing ca. 0.015 ppm selenium) when a small number of chicks (ca. 13%) had exudative diathesis (ED). By 24 hr, the high PZ51 dose (320 ppm) delayed the onset of ED compared to untreated controls. Similarly, vitamin E-deficient chicks fed diets containing 0, 80, 160, 320, 640 or 1280 ppm PZ51 and supplemented with 0.04 ppm selenium showed ED in inverse proportion to log PZ51 dose. Plasma and liver post-mitochondrial supernatant samples from these chicks also exhibited log-linear relationships between dietary PZ51 level and selenium content or SeGSHpx-like activity. The amount of SeGSHpx-like activity for chicks given PZ51 above that determined for untreated chicks was extractable into ethanol, indicating that those PZ51-associated increases were not due to protein-bound selenium or SeGSHpx. This suggests that selenium from PZ51 was not available to support synthesis of SeGSHpx. Dietary PZ51 (1280 ppm) or selenium (0.1 ppm) alone or in combination decreased the acute lethalities of nitrofurantoin or paraquat in vitamin E-adequate chicks. The results indicate that SeGSHpx-like activity in selenium-deficient chicks is increased by oral administration of PZ51, which appears to mimic the true enzyme by affording protection against clinical signs of selenium deficiency (i.e. ED) and pro-oxidant drug lethality.