title: Carbocyanine dyes with long alkyl side-chains: broad spectrum inhibitors of mitochondrial electron transport chain activity.
abstract: Certain indocarbocyanine, thiacarbocyanine, and oxacarbocyanine dyes possessing short alkyl side-chains (one to five carbons) are potent inhibitors of mammalian mitochondrial NADH-ubiquinone reductase (EC 1.6.99.3) activity (Anderson et al., Biochem Pharmacol 41: 677-684, 1991; Anderson et al., Biochem Pharmacol 45: 691-696, 1993; Anderson et al., Biochem Pharmacol 45: 2115-2122, 1993), and act similarly to rotenone. This study examines the inhibitory capacities of twelve other carbocyanine dyes (six indocarbocyanines, four oxacarbocyanines, and two thiacarbocyanines) possessing long alkyl side-chains (seven to eighteen carbons with both saturated and unsaturated side-chains) on mitochondrial NADH, succinate and cytochrome c oxidase activities. Three of the indocarbocyanines inhibited electron transport chain activity, while three were non-inhibitory. Two of the oxacarbocyanines also inhibited electron transport chain activity, while the other two were without effect. Both the thiacarbocyanines were non-inhibitory. In contrast to previous studies, the long alkyl side-chain carbocyanines exhibited a broad spectrum of inhibition of respiratory chain activity, affecting either oxidation of all three substrates or of NADH and cytochrome c, rather than specific inhibition of mitochondrial NADH-ubiquinone reductase activity, indicating that there could be multiple binding sites for these compounds. The five inhibitory long side-chain carbocyanines also inhibited reduction of ferricyanide and coenzyme Q1 by NADH, using submitochondrial particles, but not when tested with purified complex I, indicating that the mitochondrial inner membrane was an integral component in their inhibitory capacity. No general correlation of side-chain length or degree of unsaturation and inhibitory capacity was discernible.
authors.affiliation: Indiana University School of Medicine, Northwest Center for Medical Education, Gary 46408, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Anderson
authors.forename: D
authors.initials: D
authors.lastname: Trgovcich-Zacok
mesh_terms: D000818:Animals; D002232:Carbocyanines / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004396:Coloring Agents / Q000737:chemistry / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D002232:Carbocyanines; D004396:Coloring Agents; D009097:Multienzyme Complexes; D010088:Oxidoreductases; C022691:succinate oxidase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I