A study of the action of hypoglycemia-producing biguanide and sulfonylurea compounds on oxidative phosphorylation.

The mechanism of the process of oxidative phosphorylation in the respiratory chain is still quite obscure. One approach to its study has involved an investigation of inhibitors of this phenomenon (l-3). Thus, by use of various inhibitory compounds of known chemical composition some knowledge may be gleaned of the sequence of reactions comprising the over-all process, and of the nature of various participating chemical groups. Previous studies by others have amply demonstrated that various biguanide compounds inhibit electron transport in the respiratory chain. These studies, however, have led to a divergence of opinion concerning the means by which such an inhibition is effected. Thus, Wick, Larson, and Serif (4) have reported that phenethylbiguanide (Nl-P-phenethylformamidinyliminourea hydrochloride) inhibited succinic oxidase activity of rat liver homogenates. The site of inhibition was localized to some point of the electron transport chain bounded by succinic dehydrogenase and reduced cytochrome c. Other studies, by Steiner and Williams (5), have suggested that cytochrome oxidase activity may be a principal site of inhibition by the biguanides and the related diguanidine compound, decamethylenediguanidine (Synthalin A). Hollunger (6) has presented evidence suggesting that decamethylenediguanidine does not act directly on the electron transport chain, but inhibits respiration in mitochondrial preparations by inhibiting the mechanism that couples the oxidation at the pyridine nucleotide-cytochrome c level with phosphorylation. Support for this thesis was derived from the observation that addition of uncoupling agents such as 2,4dinitrophenol reversed inhibition of respiration by decamethylenediguanidine. These original observations of Hollunger clearly outlined the potentialities of various guanidine derivatives as unique inhibitors of oxidative phosphorylation and form a basis for subsequent developments in this area. Ungar, Psychoyos and Hall (7) have reported that 2,4-dinitrophenol reversed inhibition of respiration by phenethylbiguanide. In this study the effects of various biguanide and sulfonylurea compounds on oxidative phosphorylation will be reported. The findings to be described may be of added interest from the standpoint of cellular mechanisms of metabolic control, since all of the