H. Barbason

CORRELATION BETWEEN TISSULAR AND DIVISION FUNCTIONS IN THE LIVER OF YOUNG RATS

The division and tissue specific functions are studied in the liver of young rats during the first post‐natal weeks. The division function is tested by the mitotic and the 3H‐thymidine labelling index, the specific tissular function by the cholesterol‐7 alpha‐hydroxylase activity. The nycthemeral rhythm is triggered simultaneously for the two functions at the 20th day of life. From this time, spontaneous or induced mitoses occur during the day (rest period) and the cholesterol‐7‐alpha‐hydroxylase during the evening (period of activity). The results are explained by the influence of the hypothalamoadrenal axis, which presents a circadian activity with a maximum in the evening.

Variations of liver cell control during diethylnitrosamine carcinogenesis

Abstract Male Wistar rats chronically treated with diethylnitrosamine (DENA) ( 80 mg/l in drinking water) develop liver carcinomas mostly after the 90 th day of treatment. Experiments were planned in order to investigate the cell kinetics of liver during the preneoplastic period (up to the 60 th day). The mitotic response of the liver was studied in various conditions: in animals treated with DENA alone and in DENA treated rats submitted to a partial hepatectomy. Furthermore, normal hepatectomized rats were treated with liver extracts obtained in various conditions (normal and DENA treated rats). The extracts were prepared in order to purify mitotic inhibiting substances (chalone activity) normally present in liver tissue. During the two first weeks of treatment, DENA induces a transient increase of mitotic index; after partial hepatectomy, the mitotic response is approximately normal. The cell divisions present during this period a normal circadian rhythm. After the 30 th day of treatment, the mitotic index decreases significantly, the response to the partial hepatectomy is reduced and the circadian rhythm of divisions is lost. During this period, glycogen retaining areas develop in the liver; no difference is observed between the response of these areas and that of adjacent parenchyma. An extract obtained from a normal liver inhibits to a large extent the 3 H-thymidine DNA label and the mitotic response induced by a partial hepatectomy. A similar extract obtained from the liver tissue taken 24 hr after hepatectomy has no inhibitory effect. Extracts from liver of rats treated during 30 and 60 days with DENA behave in the same way as an extract from regenerating liver and produce no inhibition. The results indicate that the preneoplastic period shows at least two successive phases. During the two first weeks, the mechanisms controlling the cell homeostasis of liver tissue seem to function normally. Later on, there seems to be an important disturbance of these mechanisms.

RELATION BETWEEN THE CIRCADIAN RHYTHMS OF MITOTIC RATE AND CHOLESTEROL‐7α‐HYDROXYLASE ACTIVITY IN THE REGENERATING LIVER

The evolution of mitoses and cholesterol‐7α‐hydroxylase activity were studied in parallel in the regenerating liver after a partial hepatectomy performed at two different hours of the nycthemeral period, i.e. 10 a.m. and 8 p.m.

Circadian Synchronization of Liver Regeneration in Adult Rats: The Role Played by Adrenal Hormones

Abstract The role played by the adrenal hormones in the regulation of liver proliferation in adult rats was investigated under various experimental conditions.

Circadian synchronization of hepatocyte proliferation in young rats: the role played by adrenal hormones

Abstract. From the 20th day to the 30th day of life, the mitotic rhythm is progressively induced by a reduction in nocturnal values, while diurnal rhythms remain unchanged. Mitotic peaks emerge at 10.00 hours.

Liver cell control after discontinuation of DENA feeding in hepatocarcinogenesis

Abstract The mitotic response following a partial hepatectomy, the nyctohemeral rhythm of these mitoses and the ‘chalone activity’ measured by the inhibitory effect of liver extracts on the normal liver regeneration have been studied in order to estimate the evolution of mitotic control in the liver of rats treated by DENA for 2, 4, 6 and 10 weeks. These parameters and the pathological lesions (preneoplastic foci, neoplastic nodules and hepatomas) have been followed up after stopping the DENA feeding. A good correlation has been found between the malignant transformation of preneoplastic foci and the breakdown of the mitotic control. In animals treated by DENA for two weeks, the homeostatic control of mitoses remains normal for a minimum of 14 months and ‘preneoplastic foci’ persist without any further malignant transformation. After DENA feeding for 4 and 6 weeks, the subsequent malignant transformation occurs as a function of the mitotic disturbance: the longer the DENA feeding, the faster the homeostatic disturbance, the earlier the conceration. After DENA treatment for 10 weeks, the homeostatic regulation is lost and the neoplastic growth is triggered at the time of the DENA feeding cessation. In this case, the pattern of canceration is the same as when DENA is given continuously up to the time of death. It is concluded that ‘preneoplastic foci’ induced during the first two weeks of treatment cannot by themselves transform into a malignant tumor. To commit them irreversibly into malignancy, a subsequent action of the carcinogen is necessary; it may consist of the irreversible breakdown of the normal homostatic regulatory mechanism of liver cell proliferation.

Influence of X-irradiation on the different stages of the cell cycle in regenerating rat liver

SummaryFive groups of rats are partially hepatectomized in the afternoon. The first is the non-irradiated control and the others are irradiated (450 R) at different post-operative delays of 1 h (hepatocytes in G0), 12 h (middle of G1), 20 h (end ofG1- beginning ofS) and 28 h (S phase).When the irradiation is performed in G0 or in G1, the same inhibition of mitotic waves, micronuclei and anatelophasic bridges index, is observed. However, the mitotic delay induced by the irradiation in G0 is completely reduced when the rats are irradiated after the middle of G1 (from the 12th post-operative hour).When the irradiation is performed in theS phase, the first mitotic wave is almost completely inhibited. On the contrary, the second mitotic wave is the same as in the other irradiated groups and the micronuclei and the bridges appear at its level.The results are discussed in the light of a possible relationship between the radiosensitivity and the different phases of the cell cycle.

Evidence of a G1regulation of circadian proliferation in mouse methylcholanthrene-induced sarcomas

Abstract In two methylcholanthrene induced sarcomas of C 57 BL male mice presenting a circadian proliferation (peak of mitoses at noon and peak of labelling indices between midnight and 4 a.m.), the authors performed per cent labelled mitosis curves every 6th hr during the 8th diurnal period of growth. The G 1 phase showed the most important variation with a significant increase in the groups receiving 3 H -thymidine at 2 a.m. The possibility that this periodic variation of G 1 phase regulates the circadian rhythm of cell proliferation is discussed.

Influence of a chronic administration of diethylnitrosamine on the relation between specific tissular and division functions in the rat liver

Abstract The evolution of the division and specific tissular functions, in the liver, which are mutually exclusive of young and partially hepatectomised adult rats, was studied during hepatic carcinogenesis induced by the chronic administration of diethylnitrosamine. The results show that one of the phenomena implicated in this chemical carcinogenesis is the deregulation of the normal equilibrium between the specific tissular and the division functions. In effect, during the preneoplasic stages, these two functions are progressively disrupted; they lose their normal exclusive relationship and their specific nychtermeral rhythms. These abnormalities are observed in the unoperated as well as partially hepatectomised rats.

MOLECULAR REGULATORY MECHANISMS OF NYCTOHEMERAL RHYTHMS IN HEPATIC CELL DIVISION AND FUNCTION

ABSTRACT Under various physiological conditions, cell division function (tested by nuclear-RNA synthesis, DNA synthesis, labelling index after tritiated thymidine administration, mitotic index) and specific hepatic function (mainly assayed by cholesterol-7α-hydroxylase activity) have been compared in the liver of the rats. In adult and young rat livers, with or without partial hepatectomy, the triggering of these two different functions presents a mutually exclusive relationship and a very pronounced circadian rhythm : the derepression of the genes coding enzymes of these two functions never occurs simultaneously and thus takes place at two different moments of the nycthemeron. The kinetics of these two function evolutions could be related by the chalone regulatory mechanisms where corticoids act as effectors.