Alkanols inhibit respiration of intact mitochondria and display cutoff similar to that measured in vivo.
Primary aliphatic alcohols from hexanol to pentadecanol were tested for their effects on the succinate-supported respiration of intact mitochondria isolated from rat liver. Alkanols were found to inhibit State 3 and uncoupled respiration. The ADP/oxygen ratios, a measure of the efficiency of oxidative phosphorylation, also were lowered, but to a lesser degree when compared on the basis of percentage of controls. Given each alkanol's nearly identical effect on State 3 and uncoupled respiration, action is not directly on ATP synthase, but earlier in the respiratory process. In agreement with many other studies of the homologous series of alkanols, potency increased with number of carbons in the chain until reaching a peak, in this case at undecanol, then tapered off to tridecanol before reaching a cutoff, at tetradecanol. If tetradecanol or longer homologs have activity, it is only after a lag phase of >15-min preincubation. All alkanols up to tridecanol also acted as uncouplers. At higher doses, hexanol inhibited State 4 rates, whereas longer chain alkanols did not, even at doses that completely eliminated respiratory control. Hexanol and decanol also were assayed against freeze-thawed (broken) mitochondria to distinguish effects on the mitochondrial substrate carrier from those on the electron transport chain. Both compounds were only weak inhibitors of respiration in broken mitochondria, suggesting that inhibition originates from interference with the dicarboxylate carrier, which must transport succinate across the mitochondrial membranes before it can be fed into complex II, rather than affecting the electron transport chain itself.
Hammond
D G
DG
Department of Environmental Science, Policy, and Management, University of California, Berkeley, USA. dhammond@altertec.org
Kubo
I
I
D000244:Adenosine Diphosphate / Q000032:analysis; D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005233:Fatty Alcohols / Q000494:pharmacology; D000441:Hexanols / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000438:Alcohols; D005233:Fatty Alcohols; D000441:Hexanols; D000244:Adenosine Diphosphate; C036260:1-hexanol; C029383:n-decyl alcohol