Abstract

Under normal circumstances the oxidative metabolism of living cells and of certain isolated systems leads to the synthesis of compounds containing high-energy phosphate bonds. These compounds are known to be essential for such functions as growth, muscle contraction, nerve conduction, etc. A number of substances are able to alter this relationship by depressing the formation of high-energy bonds without depressing simultaneously the oxygen consumption of the system. This dissociation of oxidation and phosphorylation is termed "uncoupling".

Many of the substances which have been shown to uncouple phosphorylation from oxidation are drugs which have been employed in experimental pharmacology and therapeutics. Whether the effectiveness of these substances as drugs is dependent upon their effectiveness as uncoupling agents is the consideration of this review. The fact that a substance has the ability to uncouple phosphorylation from oxidation does not indicate that it is devoid of other fundamental actions. The relative importance of uncoupling as a mechanism of action will differ, of course, with different drugs. That uncoupling is of major importance in the action of certain drugs is at present a most attractive hypothesis.

With each succeeding step in our inquiry, our questions become more sophisticated and the answers to the questions become more specific. At first it was sufficient to say that certain drugs acted by "interfering with oxidation". Further study leads to the differentiation of substances which depress both oxygen consumption and phosphorylation from substances which depress phosphorylation but leave oxygen consumption relatively unaffected.

Study of these latter substances, the uncoupling agents, reveals further subgrouping: 1) those agents which stimulate oxygen consumption and are insensitive to magnesium ion changes (e.g., dinitrophenol) and 2) agents which do not stimulate oxygen consumption while depressing phosphorylation and whose action is reversed by magnesium ions (e.g., the tetracyclines). The significance of this difference remains to be explained.

Further study and formulation will surely reveal some of our present concepts to be naive. But so long as we consider the orderly flow of energy through cellular systems essential to normal function, we may consider important any agent capable of diverting this energy stream. It is from this frame of reference that the author has reviewed the phenomenon of uncoupling.