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Plasma Membrane Changes of Liver and Morris Hepatoma Induced by Retinol in Rats¹

Biochemisches Institut der Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Strasse 7, D-7800 Freiburg i. Breisgau [R. B.], and Institut für Molekularbiologie und Biochemie der Freien Universität Berlin, Arnimallee 22, D-1000 Berlin (Dahlem) 33 [W. R.], West Germany

The uptake and binding of p.o.-administered labeled all-trans-retinol was studied in vivo in rats bearing nine different types of Morris hepatomas. Radioactivity was found in acid-precipitable and acid-soluble fractions of serum, liver, and the respective tumor. In the different types of Morris hepatomas, the uptake of retinol was found to be decreased. Depending on their growth rates, the tumors accumulated 1.6 to 50% of the radioactivity determined in the respective host liver. A linear correlation was obtained when the increasing growth rates were plotted logarithmically versus the decreasing uptake rates of the vitamin. Evidently, the decreased uptake of retinol is a common feature of Morris hepatomas and seems to be related to malignant transformation and not to increased growth, because in the regenerating liver an increase of the uptake of p.o.-administered retinol was found.

A 67% decrease in the incorporation rate of labeled L-fucose and a simultaneously increased turnover of protein-bound L-fucose were the major alterations of the fucoprotein metabolism in the plasma membrane fraction of the liver induced by high doses of retinol (1.5 x 10⁶ IU all-trans-retinol per kg of body weight). The half-life of protein-bound L-fucose was 23 hr in retinol-treated rats, whereas in pair-fed control animals it was 41 hr. However, in the cytosolic fraction, the half-life of protein-bound L-fucose increased from 36 hr to 110 hr by feeding retinol.

Protein synthesis in retinol-treated rats measured by labeled L-methionine incorporation was unchanged in liver, hepatoma, and serum protein during the first hr after the pulse. However, 2 hr after the L-methionine pulse, an additional increase of the incorporation rate was observed.

Fluorographic analysis of the plasma membrane polypeptides revealed characteristic changes in the labeling pattern after labeling with L-fucose in vivo. These alterations comprise shifts of bands in the apparent molecular weight range of 30,000 to 220,000. In the plasma membrane fraction of Morris hepatoma 9121, only minimal changes were seen, although 70 IU of vitamin A per mg protein were found in the tumor 24 hr after feeding 1.5 x 10⁶ IU/kg of body weight.

This study indicates that the increased hepatic secretory activity after high doses of retinol leads to rapid turnover of incompletely fucosylated glycoproteins of the plasma membrane. The subsequent alterations in the glycosylation pattern as revealed by labeling with L-fucose in vivo are not detectable in the tumor plasma membrane. Therefore, the tumor plasma membrane is not the main target organelle of retinol. Possibly, changes in the host rather than in the tumor itself may be responsible for the anticarcinogenic effect of retinol and the retinoids.

¹ Dedicated to Professor Dr. Helmut Holzer on the occasion of his 60th birthday.

This work was supported by the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg (SFB 46 and Bu 364/1), and by the Deutsche Forschungs- und Versuchsanstalt für Luft- und Raumfahrt, Köln, West Germany.

² To whom requests for reprints should be addressed, at Medizinische Klinik der Albert-Ludwigs-Universität, Hugstetter Strasse 55, D-7800 Freiburg, West Germany.

Received 8/19/81. Accepted 3/10/82.