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Effects of a Choline-devoid Diet on the Emergence of -Glutamyltranspeptidase-positive Foci in the Liver of Carcinogen-treated Rats¹

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 [H. S., M. A. S., S. L. K., B. L.], and Department of Pathology, University of California, San Diego, La Jolla, California 92093 [S. S.]

Using the procedure of Solt and Farber for the rapid induction of foci of altered hepatocytes, we investigated the effect of a choline-devoid (CD) diet on the emergence of such foci in the liver of diethylnitrosamine (DEN)-treated rats.

After injection of a single dose of DEN into male Sprague-Dawley rats, feeding a CD diet containing acetylaminofluorene resulted in many more foci of altered -glutamyltranspeptidase (GGT)-positive hepatocytes than did feeding a choline-supplemented diet containing AAF. On the other hand, an approximately equal number of foci developed in rats given injections of a single dose of DEN while on either a plain CD or a plain choline-supplemented diet and subjected thereafter to a partial hepatectomy while being fed a choline-supplemented diet containing acetylaminofluorene. After immunofluorescence staining of liver sections, most -fetoprotein (AFP)-positive cells were oval and/or intermediate cells scattered in the parenchyma and in the vicinity of the foci of GGT-positive hepatocytes, as well as an occasional cell in newly formed ductules. On the other hand, foci of GGT-positive hepatocytes were consistently AFP negative. Oval and/or intermediate cells, as well as hepatocytes in the foci, stained positively for albumin. Levels of plasma GGT correlated positively with the number of GGT-positive foci in the liver, whereas serum concentrations of AFP showed no such a correlation.

The results obtained indicate that feeding a CD diet strongly promotes the evolution of initiated cells to foci of altered GGT-positive hepatocytes but has no effect on initiation of liver cells by DEN. The lack of AFP in the cells of the foci suggests the possibility that more than one pathway exists in the development of hepatocellular carcinomas.

¹ This study was supported in part by Research Grant CA-23449 and CA-21230 from the National Cancer Institute and grants from the Samuel and Emma Winters Foundation.

² To whom requests for reprints should be addressed, at Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. 15261.

Received 1/29/79. Accepted 3/29/79.