THE EFFECT OF ADMINISTRATION OF FK506 ON DELAYED REGENERATION IN FLUSHED PARTIALLY HEPATECTOMIZED LIVERS

It has been shown previously that liver regeneration after partial hep atectomy in rats is delayed if the liver is subjected to either concur rent ischaemia, flushing with cold solution, or grafting. We have show n recently that treatment with CsA preoperatively overcomes the suppre ssive effect of flushing and returns the regenerative response to a no rmal time scale. The present study was designed to investigate whether ad ministration of FK506 would also return the observed delayed regen erative response to normal. Long-Evans rats weighing 250-350 g were su bjected to standard 68% partial hepatectomy. Group 1 had no further tr eatment; in group 2, the liver remnant was flushed with 10 ml cold (4 degrees C) Ringers lactate solution, and in group 3, FK506 (1 mg/kg/da y) was administered by intramuscular injection for 3 days before the p artial hepatectomy and flushing as in group 2; a final dose was given after completion of the procedures. Animals were killed in sets of 6 p er group at 4, 24, 48, 72, and 96 hr after surgery and blood samples w ere taken for measurement of plasma aspartate aminotransferase. Liver biopsies were analyzed for measurement of thymidine kinase and ornithi ne decarboxylase activity and for counting of mitotic figures. While t he highest recorded thymidine kinase activity occurred in group 1 at 2 4 hr, this was delayed to 48 hr in both groups 2 and 3 and counts rema ined high up to 96 hr in group 3. Mitotic indices were only significan tly elevated (compared with group 1 at 96 hr), while ornithine decarbo xylase activity did not correlate with these changes being significant ly lower than in groups 2 and 3 at 4 hr and in group 3 also at 24 hr. Plasma aspartate aminotransferase was also significantly higher in gro up 3. It is concluded that the administration of FK506 preoperatively to rats subjected to partial hepatectomy and flushing did not restore the delayed regenerative response to normal but enhanced the response (as measured by thymidine kinase but not by mitotic indices) which com menced at 48 hr and was still present at 96 hr.