Investigation of the role of serum lipoprotein-associated peroxides in Adriamycin cardiotoxicity. Release of reduced glutathione from rat hearts perfused with lipase-hydrolyzed very low density lipoprotein fractions obtained from Adriamycin-treated and control rats.
In a previous study, we demonstrated that the serum of rats treated chronically with the anticancer agent Adriamycin contains lipid peroxides associated with neutral lipids (W. S. Thayer, Biochem Pharmacol 33: 2259-2263, 1984). In the present study, hearts from untreated control rats were perfused with medium containing serum or very low density lipoprotein (VLDL) fractions obtained from either Adriamycin-treated rats or control rats. Release of endogenous glutathione from the perfused heart was tested to evaluate possible metabolism of the serum lipid peroxides through the glutathione peroxidase/glutathione reductase redox cycle. Perfusion with lipoprotein lipase-hydrolyzed serum or VLDL caused glutathione release, the extent of which increased with increasing VLDL concentration in the perfusate. The effect was not unique for VLDL from Adriamycin-treated rats, but instead appeared to be a more general phenomenon since it was also observed with VLDL from control rats. Glutathione was released in the reduced form (GSH), rather than the oxidized form (GSSG) observed during perfusions with model peroxides. Pretreatment of the VLDL with lipoprotein lipase in vitro prior to perfusion was necessary in order to obtain GSH release. Neither lipase alone nor palmitate in the absence of lipase was as effective in promoting GSH release. Simultaneous release of lactate dehydrogenase was quantitatively less than that of GSH. The results suggest an action of components of serum VLDL on cardiac membrane permeability. Peroxide metabolism-linked perturbation of the cardiac glutathione redox cycle does not appear to be the mode of action for the serum lipid peroxides found in Adriamycin-treated rats.
Thayer
W S
WS
Department of Pathology, Hahnemann University, School of Medicine, Philadelphia, PA 19102.
D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008049:Lipase / Q000378:metabolism*; D008054:Lipid Peroxides / Q000097:blood / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D008079:Lipoproteins, VLDL; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D008049:Lipase; D005978:Glutathione