Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats.
The effects of chloroacetaldehyde (CAA) and methylene blue, both alone and together, on mitochondrial metabolism, hepatic glutathione content, and bile flow were investigated in rats. Oxidation of [1-14C]palmitic acid, [1-14C]octanoic acid, and [1,4-14C]succinic acid allowed for the differentiation between carnitine-dependent long-chain fatty acid metabolism, medium chain fatty acid oxidation, and citric acid cycle activity, respectively. CAA, a metabolite of the anticancer drug ifosfamide, which may be responsible for ifosfamide-induced encephalopathy, inhibited palmitic acid metabolism but not octanoic or succinic acid oxidation, depleted hepatic glutathione, and stimulated bile flow. Methylene blue, which is clinically used to either prevent or reverse ifosfamide-associated encephalopathy, markedly stimulated palmitic acid oxidation either in the presence or absence of CAA, but did not affect the oxidation of octanoic and succinic acid or hepatic glutathione. Taken together, this study demonstrates that CAA inhibits palmitic acid metabolism. Methylene blue stimulates long-chain fatty acid oxidation, most likely by facilitating the translocation of fatty acids into mitochondria, and compensates for the CAA effect in vivo.
Visarius
T M
TM
Department of Clinical Pharmacology, University of Bern, Switzerland.
Stucki
J W
JW
Lauterburg
B H
BH
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001646:Bile / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism; D004396:Coloring Agents / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008751:Methylene Blue / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000378:metabolism
D002210:Caprylates; D004396:Coloring Agents; D005227:Fatty Acids; D019308:Palmitic Acid; D019802:Succinic Acid; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D008751:Methylene Blue