Effect of salicylic acid and diclofenac on the medium-chain and long-chain acyl-CoA formation in the liver and brain of mouse.
Medium-chain and long-chain acyl-CoA esters are key metabolites in fatty acid metabolism. Effects of salicylic acid on the in vivo formation of acyl-CoAs in mouse liver and brain were investigated. Further, inhibition of the medium-chain and long-chain acyl-CoA synthetases by salicylic acid and diclofenac was determined in mouse liver and brain mitochondria. Acyl-CoA esters were analyzed by liquid chromatography-tandem mass spectrometry. The amounts of medium-chain acyl-CoAs (C(6), C(8) and C(10)) were less than long-chain acyl-CoAs (C(16:0), C(18:0), C(18:1) and C(20:4)) in both liver and brain. The administration of salicylic acid decreased the levels of both the medium-chain (C(6), C(8) and C(10)) and long-chain acyl-CoAs (C(16:0), C(18:0), C(18:1) and C(20:4)) in liver. In brain, however, only long-chain acyl-CoAs were decreased. The level of salicylyl-CoA detected in brain was about 12% of that in liver. Salicylic acid had a strong inhibitory activity (IC(50) = 0.1 mm) for the liver mitochondrial formation of hexanoyl-CoA from hexanoic acid, whereas diclofenac was weak (IC(50) = 4.4 mm). In contrast, diclofenac (IC(50) = 1.4 mm) inhibited the liver mitochondrial long-chain acyl-CoA synthetases more potently than salicylic acid (IC(50) = 25.5 mm). Similar inhibitory activities for the acyl-CoA synthetases were obtained in the case of the brain and liver mitochondria, except for the weak inhibition of brain medium-chain acyl-CoA synthetases by salicylic acid (IC(50) = 1.8 mm). These findings suggest that salicylic acid and diclofenac exhibit different mechanisms of inhibition of fatty acid metabolism depending on the length of the acyl chain and tissues, and they may contribute to the further understanding of the toxic effects associated with these drugs.
Kasuya
Fumiyo
F
Kobegakuin University, Minatojima, chuo-ku, Kobe, Japan. kasuya@pharm.kobegakuin.ac.jp
Kazumi
Maya
M
Tatsuki
Takao
T
Suzuki
Risa
R
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D004008:Diclofenac / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005508:Food Deprivation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D020156:Salicylic Acid / Q000009:adverse effects* / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization
D000214:Acyl Coenzyme A; D005227:Fatty Acids; D004008:Diclofenac; D003066:Coenzyme A Ligases; D020156:Salicylic Acid