Inhibition of calcium accumulation by the sarcoplasmic reticulum: a putative mechanism for the cardiotoxicity of adriamycin.
The aim of this study was to examine the effect of adriamycin (ADR) on calcium accumulation by the sarcoplasmic reticulum (SR). Chemical skinning of cultured rat myocardial cells compromised the barrier function of the cell membrane and thus permitted direct exposure of mitochondrial and non-mitochondrial sites to ADR. In the presence of ATP, and sodium azide, mitochondrial calcium accumulation was negligible. Furthermore, it has previously been shown that non-mitochondrial calcium accumulation is mediated mainly by the SR under these conditions. Incubation with 10 microM ADR for 2 hr reduced the level of calcium accumulation by the SR by 50%. A similar effect was obtained after 24 hr incubation with 1 microM ADR. The addition of ferric iron to the culture medium further reduced the level of calcium accumulation. Neither vitamin E nor beta-carotene affected calcium accumulation by the SR. These results suggest that ADR interferes with the calcium accumulation activity of the SR and that ferric iron potentiates this effect.
Halili-Rutman
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I
The Otto Meyerhoff Drug Receptor Center, Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Hershko
C
C
Link
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G
Rutman
A J
AJ
Shainberg
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D005290:Ferric Compounds / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008929:Mitochondria, Heart / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D005290:Ferric Compounds; D004317:Doxorubicin; D002118:Calcium