The mechanism of lactitol (NS-4) in inducing adrenomedullary proliferative lesion in rats.

We used 13-week repeated oral administration of lactitol as part of a study to clarify the mechanism by which lactitol induces the proliferation of adrenomedullary chromaffin cells. There was a marked increase in urinary calcium (Ca) excretion even though the lactitol administration had no effect on the blood Ca level. A tendency for an increase in adrenal venous blood epinephrine (EPI) and norepinephrine (NE) concentrations was seen. Organ weight measurement of adrenal glands revealed a tendency for an increase in absolute weight and a significant increase in relative weight. Morphometric analysis of adrenomedullary chromaffin cells showed a tendency for an increased total cell volume and a decreased numerical density; but, there was no conspicuous change in the total cell number. Determinations of the anti-bromodeoxyuridine (BrdU) and antiproliferative cell nuclear antigen (PCNA) antibody-positive cell counts showed a tendency for an increased proliferation rate for adrenomedullary chromaffin cells. Electron microscopy showed a slight increase in the number of Golgi apparatuses in these cells. Because the marked increase in urinary Ca excretion was concomitant with morphological changes that suggested the hyperfunction of chromaffin cells in the adrenal medulla and a tendency for an increased cell proliferation rate, we assume that persistent hyperfunction of the adrenomedullary chromaffin cells, which was mediated by enhanced Ca absorption from the intestinal tract, may have induced proliferative lesion.