Thiol oxidation and inhibition of Ca-ATPase by adriamycin in rabbit heart microsomes.
Incubation of rabbit heart microsomes with Adriamycin and NADPH resulted in the oxidation of approximately 25% of protein thiols and 66% inhibition of Ca-ATPase activity. Thiol oxidation and Ca-ATPase inactivation were iron-dependent and could be catalysed by ferritin. Removal of contaminating catalase revealed that both processes required H2O2 which could be supplied by O2 under aerobic conditions. However, O2- was not involved. Butylated hydroxytoluene (BHT), alpha-tocopherol and beta-carotene inhibited lipid peroxidation of microsomes, but did not inhibit thiol oxidation or the inactivation of Ca-ATPase. Likewise, the hydroxyl radical scavengers benzoate, formate and mannitol were not inhibitory. Glutathione (GSH), however, prevented inactivation of Ca-ATPase. It is concluded that Adriamycin-enhanced redox reactions involving iron and H2O2 are responsible for oxidizing microsomal thiol groups and inhibition of Ca-ATPase. Disruption of Ca transport within the myocyte by this process could contribute to the cardiotoxicity of Adriamycin.
Vile
G
G
Department of Pathology, Christchurch School of Medicine, New Zealand.
Winterbourn
C
C
D000818:Animals; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D002338:Carotenoids / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D005293:Ferritins / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000648:ultrastructure*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D011817:Rabbits; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology; D019207:beta Carotene
D006878:Hydroxides; D013438:Sulfhydryl Compounds; D019207:beta Carotene; D013481:Superoxides; D014810:Vitamin E; D002084:Butylated Hydroxytoluene; D017665:Hydroxyl Radical; D002338:Carotenoids; D009249:NADP; D004317:Doxorubicin; D005293:Ferritins; D006861:Hydrogen Peroxide; D007501:Iron; D000252:Calcium-Transporting ATPases; D005978:Glutathione; D010100:Oxygen