Potentiation of adriamycin toxicity by ethanol in perfused rat liver.
Adriamycin, which has a quinone nucleus, damages periportal regions of the lobule in perfused rat liver in an oxygen-dependent manner, presumably by redox cycling. Because redox cycling requires reducing equivalents, we investigated whether ethanol, which generates NADH via alcohol dehydrogenase, would increase hepatotoxicity due to concentrations of adriamycin which by themselves were not toxic in perfused rat liver. Perfusion with adriamycin (100 microM) alone did not significantly alter oxygen uptake or cell death evaluated by release of lactate dehydrogenase or uptake of trypan blue. In contrast, oxygen uptake due to adriamycin was increased about 35 mumol/g/hr and lactate dehydrogenase release was elevated to values around 240 U/g/hr in the presence of ethanol (10 mM). As expected, ethanol increased NADH fluorescence detected from the liver surface due to reduction of NAD+ in a concentration-dependent manner (half-maximal effect = ca. 1 mM). The increase in NADH fluorescence due to ethanol and the stimulation of oxygen uptake due to adriamycin had similar dependencies on ethanol concentration. Upon infusion of adriamycin, oxygen uptake increased concomitantly with a decrease in NADH fluorescence, most likely due to utilization of NADH. The half-maximal change in both processes also occurred with concentrations of ethanol around 1 mM. Furthermore, methylpyrazole (4 mM), an alcohol dehydrogenase inhibitor, prevented the increase in NADH fluorescence due to ethanol as well as the stimulation of oxygen uptake due to adriamycin in the presence of ethanol. Ethylhexanol, another agent which increased NADH, also potentiated oxygen uptake due to adriamycin.(ABSTRACT TRUNCATED AT 250 WORDS)
Liu
Y
Y
Department of Pharmacology, University of North Carolina, Chapel Hill.
Thurman
R G
RG
D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000032:analysis; D008862:Microsomes, Liver / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D008954:Models, Biological; D009243:NAD / Q000032:analysis; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D009243:NAD; D000431:Ethanol; D008315:Malondialdehyde; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D010100:Oxygen