TRANSPLANTATION OF NORMAL HEPATOCYTES MODULATES THE DEVELOPMENT OF CHRONIC LIVER-LESIONS INDUCED BY A PYRROLIZIDINE ALKALOID, LASIOCARPINE

Lasiocarpine (LC), a pyrrolizidine alkaloid, is able to induce a serie s of chronic and progressive lesions in rat liver, including a long-la sting block in the cell cycle, the appearance of enlarged hepatocytes (megalacytosis), fibrosis, cirrhosis and malignant neoplasms. In this study the effect of transplantation of normal hepatocytes on the devel opment of LC-induced chronic lesions in rat liver was examined. Two-mo nth-old male Fischer 344 rats were given a single dose of LC (80 mu mo l/kg i.p.). Four weeks later all animals were subjected to 2/3 partial hepatectomy (PH)., In addition, at the time of PH one group of rats w ere transplanted with normal hepatocytes isolated from a syngeneic don or (10(6) cells/rat via the portal vein), while the other group receiv ed only the culture medium. All rats were killed 14 weeks after the op eration. Grossly, the liver of rats exposed to LC followed by PH with no transplantation of normal hepatocytes was small in size (% liver wt /body wt 1.66 +/- 0.08) and exhibited a few whitish nodules. Histologi cally, similar to 88% of the liver section was occupied by enlarged he patocytes and hepatocyte nodules composed of smaller hepatocytes devel oped in every animal in this group. In addition, extensive bile ductul ar proliferation was present. However, the liver of rats that were sim ilarly treated but received normal hepatocytes were significantly larg er in size (% liver wt/ body wt 2.16 +/- 0.07) and were almost complet ely free of megalocytosis, bile ductular proliferation and hepatocyte nodules. These findings indicate that transplantation of normal hepato cytes is able to modulate the development of chronic liver lesions ind uced by LC and may be relevant to the pathogenesis of progressive live r diseases such as neoplasia and cirrhosis.