Lipid peroxidation induced by adriamycin in linolenic acid-loaded cultured hepatocytes.
Addition of more than 10 microM of adriamycin to cultured rat hepatocytes loaded with alpha-linolenic acid (linolenic acid-loaded hepatocytes) caused marked lipid peroxidation as measured by an accumulation of malondialdehyde during a 9 hr incubation. After addition of 50 microM of adriamycin to linolenic acid-loaded hepatocytes, malondialdehyde accumulation significantly increased at 3 hr, followed by cellular reduced glutathione decrease and lactate dehydrogenase leakage after 6 hr. Inhibition of adriamycin-induced lipid peroxidation by addition of N,N'-diphenyl-p-phenylenediamine or alpha-tocopherol, both lipid radical scavengers, or deferoxamine, which is a Fe ion chelator, prevented both glutathione decrease and lactate dehydrogenase leakage, indicating that lipid peroxidation caused cellular damage to linolenic acid-loaded hepatocytes exposed to adriamycin. The effect of SKF 525-A, which is a cytochrome P450 inhibitor, on adriamycin-induced lipid peroxidation and on 7-ethoxycoumarin O-deethylase activity was determined by 6 hr incubation of linolenic acid-loaded cells. Addition of SKF 525-A suppressed adriamycin-induced lipid peroxidation comparably with its 7-ethoxy-coumarin 0-deethylase inhibitory activity. These results suggest that cytochrome P450 contributes to the one-electron bioreduction of adriamycin into its semiquinone radical in rat hepatocytes.
Furuno
K
K
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan.
Suetsugu
T
T
Shimomichi
K
K
Tsuruta
Y
Y
Sugihara
N
N
D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014810:Vitamin E / Q000494:pharmacology; D017962:alpha-Linolenic Acid / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010655:Phenylenediamines; D017962:alpha-Linolenic Acid; D014810:Vitamin E; D008315:Malondialdehyde; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C004845:N,N'-diphenyl-4-phenylenediamine; D007770:L-Lactate Dehydrogenase; D015660:7-Alkoxycoumarin O-Dealkylase; D003676:Deferoxamine