The duclauxin derivatives xenoclauxin and desacetylduclauxin were examined for their effects on the growth of L-1210 murine leukemia cells, on the induction of DNA repair in the rat and mouse hepatocyte primary culture (HPC/DNA repair test), and on oxidative phosphorylation in mitochondria from rat livers in comparison to duclauxin. Both derivatives inhibited the growth of L-1210 culture cells as strongly as duclauxin. Duclauxin derivatives were negative in the HPC/DNA repair test. Xenoclauxin exhibited a potent uncoupling effect accompanying a marked depression of state 3 respiration of mitochondria in a similar fashion to that of duclauxin. Desacetylduclauxin significantly inhibited the state 3 respiration without causing uncoupling of oxidative phosphorylation in mitochondria. These results strongly suggest that xenoclauxin and desacetylduclauxin from Penicillium duclauxii are not genotoxic but are cytotoxic mainly due to their potent inhibition of ATP synthesis in mitochondria.
The A'-desaturase system in liver microsome from rats treated chronically with ethanol was studied. Stearoyl-CoA desaturase activity decreased by 80% and palmitoyl-CoA desaturase activity was not detectable in microsomes from ethanol-fed rats, while activities of electron transport components such as NADH-cytochrome c and NADH-ferricyanide reductases remained unchanged. However, chronic ethanol administration resulted in an adaptive induction of the activity of NADPH-cytochrome c reductase and the contents of cytochrome by and P-450. The activity of the terminal component (cyanide-sensitive factor; CSF) of the desaturase system was greatly depressed by ethanol treatment. The NADH/NAD ratio in microsomes of ethanol-fed rats increased over 2-fold. These results suggest that, during chronic ethanol ingestion, decreased activities of A'-desaturases are due mainly to a decreased content of the terminal component of the desaturase system.
The interaction between BW755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline), a potent inhibitor of both lipoxygenase and cyclo-oxygenase, and respiratory chain in mitochondria and electron transport particles (ETP) from rat livers was examined. BW755C accelerated the oxygen uptake by mitochondria without the addition of substrate for the respiratory chain. Spectrophotometric study revealed that BW755C was quickly oxidized by cytochrome oxidase in mitochondria to a compound possessing an absorption maximum at 524 nm. p-Phenylenediamine (p-diaminobenzene, PPDA), which, like BW755C, serves as an electron donor to cytochrome oxidase, was shown to inhibit the generation of active oxygen in macrophages; the inhibition was stronger than that of BW755C. These results strongly suggest that the oxidative conversion of BW755C by mitochondrial cytochrome oxidase is associated with its potentially inhibitory action on the active oxygen-generating system in phagocytes.
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