Lobule-dependent zonal measurement (LZM) method for the determination of cell proliferation in the liver

Using the conventional method of measurement (randomly distributed fields) there is a risk of overlooking a biologically relevant effect due to the different zonal expression of cell proliferation. Therefore a lobule-dependent zonal measurement (LZM) method was developed that guaranteed the independent evaluation of the hepatic zones in lobules of a comparable size. With this method, applied in a 3-month-study, a statistically significant increase in cell proliferation after one week (71%) and a distinct increase after six weeks (49%) and thirteen weeks (32%) of exposure could be proved, whereas the conventional method revealed after one week only a slight increase (22%), after six weeks a distinct but not statistically significant increase (56%) and after thirteen weeks even a decrease of 24%. In comparison, the LZM-method revealed a panlobular increase of cell proliferation after one week of administration, that shifted to the periportal region after six and thirteen weeks representing the target zone as it was shown by electronmicroscopy later on. Since the test substance evoked an increased tumor incidence in both sexes in a lif-span study, the enhanced cell proliferation, in our case especially in the periportal area, seems to be a key mechanism in tumor development. These data confirm that the, LZM-method represents a very sensitive and stable method in the evaluation of cell proliferation in the liver.