[Reversible hyperplasia and hypertrophy of the mouse liver induced by a functional charge with phenobarbital]

Abstract

Introduction: Administration of phenobarbital to rats and mice is well known to cause enlargement of the liver, where the drug is metabolized by hydroxylation and oxydation. The increase of the liver weight is thought to be due to and enlargement of the individual hepatocytes (hypertrophy) caused by an augmentation of the smooth endoplasmic reticulum, as well as to cell multiplication (hyperplasia). The present investigation deals with the nuclear DNA content of mouse hepatocytes during and after administration of different doses of phenobarbital. The data are related to liver weight with due consideration of mitotic activity and cell loss by necrobiosis.

Material and methods: 172 five to six weeks old male albino NMRI mice with a body weight of 23 to 33 gms were randomly divided into four groups, one of which served as the controls. The three test groups received 75 mg and 150 mg phenobarbital per 1 kg body weight intraperitoneally once every day for a total of 10 days. Thereafter the administration of the drug was discontinued. Beginning with the third day of the experiment 3 animals of each group were sacrificed by exsanguination every secound day after their body weight had been carefully determined. Then the liver weights were measured. The nuclear DNA content of the hepatocytes was determined from liver smears by means of acriflavine-Feulgen fluorescence cytophotometry. The number of mitotic figures and of necrobiotic liver cells was counted in histologic sections.

Results: With animals receiving 150 mg and 100 mg phenobarbital per 1 kg body weight a rapid increase of the relative liver weight (up to 74% above the controls) was observed, which was reduced back to normal levels within 10 days after discontinuation of the drug. Parallel with the increase of the liver weight a striking DNA-polyploidisation of the liver nuclei occurred which proved to be reversible during the reduction phase. Mitotic figures were found only in the initial phase of the experiment (third to fifth day), while the number of necrobiotic hepatocytes was increased after the drug was discontinued. Similar but markedly less pronounced effects were encountered with animals of the 75 group.

Discussion: It is concluded that the increase of the liver weight of mice after phenobarbital administration is partly due to cell multiplication (hyperplasia) - as is shown by a high number of mitotic figures in the initial phase of the experiment-, partly due to the enlargement of hepatocytes with concommitant polyploidisation of the muclei (hypertrophy). When the drug administration is discontinued the liver weights return to normal levels within 10 days. Since at the same time the number of high-ploidy nuclei is reduced with no evidence of an increased mitotic activity, the reduction of the liver weight should be partly caused by an elimination of high-ploidy hepatocytes, which are no longer required after the hyperfunctional stimulus has ceased...