In nature it is known that juglone retards the growth of competing plants under walnut trees (Jose and Gillispie, 1998). Since uncouplers
usually break down the proton electrochemical gradient in chloroplasts in the same way as in mitochondria, this could be the likely reason why juglone is also toxic to plants. Juglone is unavoidably ingested by humans when walnut extracts are used in popular medicine and it is worth to examine how this could affect the general physiology (Bell, 1981, Jin, 2010 and Mahoney et al., 2000). Uncouplers were used in the past as weight loss agents, especially 2,4-dinitrophenol. Since uncouplers reduce the efficiency of energy transduction in the mitochondrial electron transport chain, more fuel has to be oxidized in order to produce CDK and cancer the same amount of ATP. This fuel comprises largely fatty acids, weight loss is thus an understandable effect of uncoupling agents. Most of them are quite dangerous due to their narrow therapeutic window, i.e., the small concentration range between mild and nearly full uncoupling. The latter is a highly toxic condition. It has been proposed that uncouplers with a wide therapeutic window would be more appropriate and less dangerous as therapeutic agents for weight loss (Lou et al., 2007). One such compound is 2,6-bis(1,1-dimethylethyl)-4-methylphenol,
more commonly known as BHT. This compound already uncouples at extremely low concentrations, 2 × 10− 12 M, but it produces U0126 ic50 only modest increases 3-mercaptopyruvate sulfurtransferase in uncoupling as its concentration
is raised to 2 μM (Lou et al., 2007). Most other uncouplers, including 2,4-dinitrophenol show a much narrower range of activity, generally comprising not much than one order of magnitude. From the results obtained in the present work it is evident that juglone must be classified as a narrow range uncoupler. In isolated mitochondria its action is exerted in the 10− 6 to 10− 5 M range. In the perfused liver, the consequences of this action are detectable in the 10− 6 to 2 × 10− 5 M range. In this particular, thus, it resembles more closely the classical uncoupler 2,4-dinitrophenol. Ingestion of high doses of juglone, consequently, presents the same risks as the ingestion of high doses of 2,4-dinitrophenol which comprise excessive compromising of ATP production, hyperthermia and even death. It should also be noted that blocking of transcription, induction of DNA damage, reduction of protein levels and induction of cell death are all effects that occur within the same concentration range as the effects observed in the present work (Paulsen and Ljungman, 2005). The use of juglone as an anticancer agent, thus, is not deprived of considerable risk if one takes into account the doses that are necessary for this action.
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