Peroxisomal β-oxidation from endogenous substrates. Demonstration through H2O2 production in the unanaesthetized mouse

Abstract

A system was developed in which it is possible to detect in vivo changes in hepatic H2O2 production, using a combination of the catalase inhibitor, 3-amino-1,2,4-triazole and methanol. In mice, starvation significantly increases hepatic H2O2 production and plasma non-esterified fatty acid concentrations. Short-term refeeding after a 24 h starvation period brings H2O2 production and plasma non-esterified fatty acid concentration back to normal in 3h. Administration of insulin 24 h after the onset of starvation normalizes H2O2 production in less than 2h and decreases non-esterified fatty acid concentration below normal values. The suppression by insulin of H2O2 production, as well as its coherence with plasma non-esterified fatty acid concentration, indicate that increased H2O2 production in starved mice reflects peroxisomal beta-oxidation.

Thioridazine: a selective inhibitor of peroxisomal β‐oxidation in vivo

“…The level of RCA reached after Th treatment is the same in fed and in fasted animals and equal to the level reached after insulin administration to fasted mice [9]. This suggests that Hz02 production from &oxidation has reached its minimum, and consequently that near therapeutic doses Th inhibits peroxisomal &oxidation completely.…”

“…Residual catalase activity (RCA) is the catalase activity that remains after inhibition by aminotriazole in combination with methanol. A lower RCA reflects a higher Hz02 production [9].…”

“…In vivo )I202 production in the liver of unanaesthetized mice can be evaluated by measuring the catalase activity which remains after inhibition of the catalase-Hz02 complex by 3-amino-1,2,4-triazole in combination with methanol [9]. In an earlier study we demonstrated that starvation causes an increased flux of fatty acids through the peroxisomal fatty acid oxidase [9].…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Finally, monounsaturated oleic acid is a better H 2 O 2 -source than palmitic acid in rat hepatocytes (Mannaerts et al, 1979) and perfused rat liver (Foerster et al, 1981). In mice, starvation increases the H 2 O 2 production by liver, likely due to increased fatty acid plasma levels ( Van den Branden et al, 1984). However, in cardiac tissue there is no change (Kerckaert and Roels, 1986).…”

“…Exposure of cells to carboxylates (or their precursors) that are desaturated by these ACOXs will generate peroxisomal H 2 O 2 . This has been shown in different systems [e.g., cells, perfused organs (Foerster et al, 1981;Handler and Thurman, 1987), and intact animals ( Van den Branden et al, 1984)] and with different types of carboxylates [e.g., medium-chain fatty acids (Skorin et al, 1992); long-chain saturated and mono-and polyunsaturated fatty acids (Mannaerts et al, 1979;Foerster et al, 1981;Chu et al, 1995;Okamoto et al, 1997)]; mediumchain dicarboxylic acids (Leighton et al, 1989); and xenobiotics such as N-(α-methylbenzyl)azelaamic acid (Yamada et al, 1986;Suzuki et al, 1990), ω-phenyl-substituted fatty acids (Yamada et al, 1987), and PCA16, a metabolite of the cytosine arabinoside antileukemic prodrug YNKO (containing a stearic acid side chain) (Yoshida et al, 1990).…”