Mitochondrial membrane-linked reactions in carcinogenesis: change in steroselective uncoupling of oxidative phosphorylation by aliphatic dicarbonyls and in the Arrhenius plot of NADH-indophenol reductase
Bryant, G.M.; Argus, M.F.; Arcos, J.C.
Gan 68(1): 89-98
1977
ISSN/ISBN: 0016-450X PMID: 405268 Document Number: 116817
Previously observed alterations in the energy transducing system of rat liver mitochondria during 3'-methyl-4-(dimethylamino)azobenzene (3'-Me-DAB) carcinogenesis were investigated using aliphatic dicarbonyl compounds as molecular probes and the effect of temperature on membrane linked NADH-indophenol reductase. The vicinal diketone, diacetyl, uncouples oxidative phosphorylation in normal rat liver mitochondria while the higher diketones, acetylacetone and acetonylacetone, are increasingly less effective in that order. Diacetyl totally abolishes respiratory control with substrates, the oxidation of which involves the NADH .fwdarw. CoQ [coenzyme Q] segment, but only partially with succinate which bypasses this segment. Diacetyl, likewise, uncouples oxidative phosphorylation in liver mitochondria from rats fed 3'-Me-DAB, but the mitochondria are most resistant to this uncoupling (in terms of the P/O ratio) at the time when the respiratory control index (determined in the absence of diacetyl) is at the dye-induced minimum. This time period is 3-4 wk of dye administration, representing the cumulative dose for tumorigenesis threshold. At this threshold period of feeding 3'-Me-DAB, discontinuities in the Arrhenius plot of mitochondrial membrane-localized NADH-indophenol reductase appear, with a return toward the control state (no break) at 8 wk, only to reappear in the plot of the enzyme from tumor mitochondria, suggesting sequential membrane phase transitions in the mitochondria during azo dye carcinogenesis.