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The Relation of the Structure of Choline-Like Compounds to Renal Antihemorrhagic Action¹

Department of Pharmacology, School of Medicine, Western Reserve University, Cleveland, Ohio

The ability of choline, betaine, dimethylthetin, and various related compounds to protect the weanling rat from the renal hemorrhagic syndrome of choline deficiency has been studied. The frequency of hemorrhagic change in the kidney is correlated better with the dietary level of choline than is the average weight of the paired kidneys. Under the conditions described, the dietary level of choline chloride required to protect 50% of the animals on experiment is about 0.04%, while 0.075% affords protection to all animals. It is noted that the kidney is protected by a lower dietary level of choline than is required for preventing the deposition of fat in the liver.

The marked renal protective action of the triethyl homologue and of the arsenic analogue of choline chloride are demonstrated. This activity, coupled with the inability of these compounds to serve as donors of a methyl group, permits the conclusion that choline acts by satisfying a requirement of the growing kidney for the intact molecule of choline and not primarily for the labile methyl group of which choline, by virtue of its conversion to betaine, is a donor. The phosphorus analogue of choline chloride is also a potent renal protective agent. In keeping with earlier findings concerning the lipotropic inactivity of the arsenic and phosphorus analogues of betaine hydrochloride, these compounds are shown to exert no renal antihemorrhagic effect.

The monoethyl and diethyl homologues of choline chloride are very effective antihemorrhagically, but the tripropyl homologue is inactive.

ß-Methylcholine chloride is about one-tenth to one-twentieth as active as choline chloride in preventing the renal hemorrhages of choline deficiency. The activity of the phosphoric acid ester of this derivative of choline, administered subcutaneously, probably is equivalent to its ß-methylcholine content.

Betaine aldehyde chloride and betaine hydrochloride are active renal antihemorrhagic (and lipotropic) agents, but the activity appears to approximate one-fourth that of choline chloride. Although some samples of -alanine betaine appeared to protect the kidneys to a slight extent, it is concluded that the pure compound is inactive in this respect as well as lipotropically. The betaine of serine is also inactive.

Dimethylthetin (the sulfur analogue of betaine) and methyl-ethylthetin are potent renal antihemorrhagic agents, while diethylthetin is inactive. The ability of the methyl-containing thetins, like betaine, to donate a methyl group for the synthesis of choline from precursors which occur in the diet or are produced metabolically is discussed.

Inactive as renal antihemorrhagic agents are the sulfuric acid ester of choline, i-inositol, and aminoethanol. The activity of dimethylaminoethanol is noted and its mechanism of action discussed.

Manuscript received 1 August 1949.