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The role played by the adrenal hormones in the regulation of liver proliferation in adult rats was investigated under various experimental conditions.In untreated control groups, cell growth was very low and endogenous corticosterone levels showed a clearly-defined circadian rhythm with a peak in the evening. Adrenalectomy depressed the level of endogenous corticosterone immediately and the growth rate of the liver increased significantly. We were able to prevent this effect by repeated injections of corticosterone at physiological doses.After a 1/3 hepatectomy and a sham-operation, the corticosterone blood level maintained its normal circadian pattern with the exception of a transient increase during the first two post-operative hours. After a hepatectomy of this kind, a negative correlation was found to exist between the adrenal hormone level and the waves of DNA synthesis; the subsequent mitoses appeared in two successive circadian waves of decreasing amplitude, a maximum value being reached in the morning. In rats submitted to a 1/3 hepatectomy and an adrenalectomy simultaneously, the endogenous corticosterone level fell significantly after a post-operative peak. The regenerating pattern was completely different from that induced by 1/3 hepatectomy alone. The rise in the labelling index began earlier and rose to significantly higher values; it was then followed by a single large mitotic wave without any circadian rhythm.These results favour the hypothesis that adrenal hormones have a significant effect on the negative control of liver regeneration. Circadian changes in the corticosterone level were responsible for the nycthemeral pattern observed in the regenerating liver after a partial hepatectomy. The results show a marked inhibition of the G,-S transition, particularly in the evening, when the endogenous corticosterone concentration was at its highest. Also discussed is the relationship between corticoids and 'chalones', which synergetically inhibit the passage from Go into the cell cycle.We have previously shown that the circadian synchronization of hepatic cell proliferation and specific enzyme activities are triggered from the 20th day of life onwards (Barbason, Van Cantfort & Houbrechts, 1974). This corresponds to the maturation and the circadian activity of

70% of the microsome‐bound cholesterol is directly accessible to cholesterol 7α‐hydroxylase in an assay in vitro. After 5 min of incubation this endogenous cholesterol makes a single pool with the exogenously added substrate and modifies its specific radioactivity. Thus, an accurate estimation of the enzymic activity should take the participation of endogenous cholesterol into account. Cholesterol 7α‐hydroxylase activity is enhanced in vitro by thiol‐containing substances like mercaptoethanol, dithiothreitol, or cysteamine. On the contrary, the enzymic activity is inhibited by heavy cations (Hg2+, Pb2+, Cu2+, Zn2+), or −SH‐blocking agents (mersalic acid, p‐chloro‐mercuribenzoic acid). Several steroids are potent inhibitors (Ki < Km) of the enzyme, among them pregnenolone and its acetate derivative and the cholesterol closely related 7‐oxocholesterol and 7‐dehydrocholesterol. The cholesterol esters are neither substrates nor inhibitors of cholesterol 7α‐hydroxylase. Only a high concentration (1 mM) of biliary acids or of their glyco or tauro derivatives inhibits cholesterol 7α‐hydroxylase. The quantitatively less important lithocholic acid and deoxycholic acid are the strongest inhibitors; the most common cholic acid does not affect the enzymic activity even at 1 mM.

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A study was designed to investigate the fate of navelbine (NVB) and its excretion routes in two cancer patients treated with tritiated NVB (30 mg/m2) by i.v. bolus injection. Plasma and red blood cell concentrations and urine and stool elimination were monitored over long periods of time. NVB plasma and urine concentrations were measured by both radioimmunoassay (RIA) and direct radioactive (RA) determination. Samples were also analyzed by high-performance liquid chromatography to evaluate the importance of NVB metabolism. Whereas the major excretion route for NVB was the stool (from 34% to 58.4% of the total dose given over 21 days), urinary excretion was low (about 21% within the same time period), corresponding mainly to that of unchanged drug. Thus, a good correlation was found between RIA and RA determinations in urine. In contrast, plasma area under the curve (AUC) values obtained after RA and RIA analysis differed markedly (AUC RIA/AUC RA = 0.23-0.31), demonstrating that a significant proportion of the plasma-circulating drug was biotransformed, mainly during the last elimination phase. This could have important pharmacological and toxicologic implications in clinical practice.