The Choline-Devoid Diet Model of Hepatocarcinogenesis in the Rat

Abstract

The notion that a choline-devoid (CD) diet is hepatocarcinogenic in the rat has already gone through two historical phases, and is at the beginning of its third (for a detailed account, see ref. 1). In 1946, Copeland and Salmon published the first of a series of papers showing the development of hepatocellular carcinomas (HCCs) in rats chronically fed a CD diet^2,3. The finding attracted much attention at the time, since the modalities of the experiments involved no addition to the diet of, or treatment of the animals with, chemical carcinogens. However, subsequent studies by Newberne et al.^4,5 cast doubts on whether the diet, and the diet alone, was responsible for the genesis of the tumors, and attributed the latter, instead, to a likely contamination of the diet with aflatoxin B1, a newly discovered⁶ and most potent hepatocarcinogen in the rat⁷. In the last few years, the question was reopened by a repetition of the original findings of Copeland and Salmon in three different laboratories^8–11. In these instances, both diets and rat’s environment were scrutinized for relevant contamination with chemical carcinogens, with negative results. At the present time, therefore, the conclusion seems unavoidable that CD diets are indeed hepatocarcinogenic, and that the genesis of the tumors resides in effects of these diets on rat liver. However, at least one primary issue awaits resolution, before the CD-diet model of hepatocarcinogenesis can be fully categorized; that is whether the diets act as complete carcinogens, able to initiate de novo liver cells, as well as to promote their evolution to cancer; or whether they merely promote the evolution to cancer of endogenous initiated cells.