Investigations on the turnover of adrenocortical mitochondria. VII. Effects of ACTH on the half-life of mitochondria from the zona reticularis of the rat adrenal cortex

Summary The half-life of mitochondria from the zona reticularis of the rat adrenal was calculated by determining the radioactivity decay curves of the mitochondrial compartment of 3H-thymidine-injected animals, using autoradiographic methods. ACTH was found to enhance significantly the half-life of the organelles.Acknowledgment. We wish to thank Miss A. Coi and Mr G. Gottardo for the skilled techical assistance. This work was partly supported by a contract with the CNR (No. 74.00226.04/115.3439).     

Effect of ethanol intake on phenytoin metabolism in volunteers.

Ingestion of ethanol, 1 g/kg, did not influence the phenytoin half-life in 5 volunteers after single i.v. administration of 3 mg/kg phenytoin. The control phenytoin half-life was 12.4 h (SD +/- 4.4); with ethanol ingestion it was 12.3 h (SD +/- 5.2).     

Effect of thiamine hydrochloride on the blood level of 2-formyl 1-methyl pyridinium oxime chloride (2-PAM.C1) in rats.

The biological half-life of 2-PAM.C1 was found to increase in female rats pretreated with thiamine hydrochloride (10 mg/kg i.m.). No such effect was observed in the male rats.     

Investigations into the effects of ACTH on the half-life of mitochondrial proteins in the rat adrenal cortex.

ACTH elongates the half-life of the mitochondrial proteins from the rat adrenal cortex, and chloramphenicol inhibits this effect of ACTH. The hypothesis is advanced that the ACTH-provoked stabilization of the adrenocortical mitochondrial proteins requires continuous mitochondrial DNA-dependent protein synthesis.     

Half-life of dehydroepiandrosterone sulfate (DHAS) during pregnancy]

During pregnancy the half-life of DHAS was measured after non tritiated DHAS infusion. At 30 weeks, the mean value obtained for DHAS half-life was 3.64 h +/- 0.74 and it was 3.67h +/- 0.38 at 38 weeks. The half-life of DHAS is shorter in pregnant than in non-pregnant women. Among 14 pathological pregnancies that we studied, 13 cases exhibited a DHAS half-life significantly longer than the average value obtained in normal pregnancies. In retarded fetal growth, the half-life of DHAS was more closely related to fetal than to placental weight.     

Effect of thiamine hydrochloride on the blood level of 2-formyl 1-methyl pyridinium oxime chloride (2-PAM.Cl) in rats

Summary The biological half-life of 2-PAM.Cl was found to increase in female rats pretreated with thiamine hydrochloride (10 mg/kg i.m.). No such effect was observed in the male rats.Dr B.L. Chowdhri very kindly synthesized the compound 2-PAM.Cl in the Department of Chemistry of this establishment for this work.The authors are thankful to Dr P.K. Ramachandran, Director, and Dr A.K. Chatterjee, Deputy Director, Defence Research and Development Establishment, Gwalior, for their keen interest in this work.     

Investigations into the effects of ACTH on the half-life of mitochondrial proteins in the rat adrenal cortex

Summary ACTH elongates the half-life of the mitochondrial proteins from the rat adrenal cortex, and chloramphenicol inhibits this effect of ACTH. The hypothesis is advanced that the ACTH-provoked stabilization of the adrenocortical mitochondrial proteins requires continuous mitochondrial DNA-dependent protein synthesis.     

Effects of chronic paralysis of chick embryo by flaxedil on the development of the neuromuscular junction]

Chronic paralysis of Chick embryos by the cholinergic antagonist flaxedil blocks the subsynaptic accumulation of acetylcholinesterase but not the formation of acetylcholine receptor cluster. Flaxedil paralysis also causes an increase of the total muscle content of acetylcholine receptor without altering the half-life of the receptor protein. The spontaneous activity of the embryon therefore "shuts off" the synthesis of extrasynpatic acetylcholine receptor.     

Proteases and proteolysis in the lysosome.

Proteins sequestered by a non-selective bulk process within the lysosomes turn over with an apparent half-life of about 8 minutes and this rapid lysosomal proteolysis is initiated by endopeptidases, in particular by the cathepsins D and L. We describe also the cathepsins B and H which show mainly exopeptidase and only low endopeptidase activity. Especially cathepsin H is most probably the only lysosomal aminopeptidase in many cell types. Additionally, the properties of other mammalian lysosomal endo- and exopeptidases are compared. Finally, we discuss some of the conditions for the action of lysosomal proteases as the low intralysosomal pH, the high part of lysosomal thiol groups and the absence of intralysosomal proteinase inhibitors.     

Extended blood half-life of monomethoxypolyethylene glycol-conjugated hen lysozyme is a key parameter controlling immunological tolerogenicity

The blood half-life of a protein is prolonged by conjugating a protein with a linear amphiphilic polymer, monomethoxypolyethylene glycol (mPEG). The conjugation gives a protein immunotolerogenicity; hence, it is likely that the long half-life is crucial for the tolerogenicity. We prepared a tolerogenic mPEG conjugate of hen egg lysozyme (mPEG_1.5-HEL), which is conjugated 1.5-fold the molecular weight of mPEG against that of HEL, and evaluated the relationship between in vivo stability and the tolerogenicity. mPEG_1.5-HEL retained immunogenicity to prime HEL-specific T cell and antibody responses and had a long blood half-life, more than 27 times that of native HEL. The tolerant state was maintained as long as mPEG_1.5-HEL was detected in sera. With a decrease in the blood mPEG_1.5-HEL level, the tolerant state returned gradually to the responsive state; however, reinjection of mPEG_1.5-HEL again restored the tolerance. Thus, the extended blood half-life of HEL by mPEG conjugation is probably vital for establishing and maintaining the tolerant states. Received 17 May 1999; accepted 1 June 1999     

Sex pheromone conversion and degradation in antennae of the silkworm mothBombyx mori L.

Summary In living antennae of the silkworm mothBombyx mori L. the pheromone compound (E, Z)-10,12-hexadecadienol and hexadecanol are enzymatically converted to their corresponding fatty aldehydes, acids and long-chain fatty acid esters. The pheromone is completely degraded at high rates in the antennae of freshly hatched moths. The polar volatile [³H]metabolites exclusively consist of tritiated water. The half-life of the pheromone is about 2.5 min in males and 0.5 min in females. Drying inactivates the enzymes responsible for pheromone oxidation.Dedicated to Professor Adolf Butenandt on the occasion of his 85th birthday     

Observations on salicyl hydroxamic acid,an experimental trypanocide

Summary The inferior in vivo efficacy of salicyl hydroxamic acid against trypanosomiasis may be explained by its short half-life, high degree of protein binding and low tissue levels.     

The role of sialic acid in determining the survival of circulating interferon

Summary Rabbit interferon has been extensively desialylated and its metabolic behaviour has been evaluated in the rabbit. The half-life of asialointerferon is significantly shorter than the native interferon and its urinary excretion becomes negligible. Moreover the rapid uptake of asialointerferon by the isolated and perfused rabbit liver, suggests a hitherto unsuspected catabolic pathway for this glycoprotein.This work was supported by a grant from the Consiglio Nazionale delle Ricerche, Roma (subproject on antiviral therapy), contract No. 76.00646.84).     

Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics

Naturally occurring polymers of N-acetylneuraminic acid (polysialic acids) are biodegradable, highly hydrophilic and have no known receptors in the body. Following intravenous injection, polysialic acids exhibit long half-lives in the blood circulation and have therefore been proposed as carriers of short-lived drugs and small peptides. In addition, shorter-chain polysialic acids can be used as a means to increase the circulatory half-life of proteins and thus serve as an alternative to the nonbiodegradable monomethoxypoly(ethylene glycol). Recent work has shown that covalent coupling of a low molecular weight polysialic acid (colominic acid) to catalase and asparaginase leads to a considerable increase of enzyme stability in the presence of proteolytic enzymes or blood plasma. Comparative studies in vivo with polysialylated and intact asparaginase revealed that polysialylation significantly increases the half-life of the enzyme. The highly hydrophilic and innocuous nature of polysialic acids renders them suitable as a means to prolong the circulation of peptides and proteins.     

The elimination of 1,5-anhydroglucitol administered to rats

Summary Rat serum contains natural 1,5-anhydroglucitol. Injected or orally administered 1,5-anhydroglucitol was efficiently reabsorbed by the renal tubuli via a mechanism which had a saturation point at high serum 1,5-anhydroglucitol levels. The compound had a slow turnover rate in the body; its half-life is approximately 3 days. The compound was readily absorbed in the gut when administered orally.     

Reduction of gallstone formation by ascorbic acid in hamsters

Summary The addition of 0.5% of ascorbic acid to the lithogenic diet of golden hamsters whose body pool was labelled with 26-¹⁴C-cholesterol, lowered the formation of gallstones, the cholesterol concentration and half-life in blood plasma and in the liver, and accelerated cholesterol transformation to bile acids.     

Antipyrine metabolism in cancer patients

Summary The metabolism of antipyrine was studied in cancer patients. Antipyrine elimination might be decreased in cancer patients. Increase in antipyrine half-life is not primarily due to the presence of a tumor but rather to the nutritional status and liver function of an individual.     

Kinetics of the pulmonary clearance of inhaled cadmium and its accumulation in rat liver and kidneys]

Pulmonary clearance rate of cadmium (Cd), inhaled in the form of an aerosol of Cd acetate, is very slow (half-life 53 days). However, results demonstrate that an important part of Cd cleared from the lung is recovered in liver and kidney. Liver binds this metal rapidly but to a limited extent, whereas renal accumulation is slow but continuous throughout the three months following exposure.     

Kinetics of BRCA1 regulation in response to UVC radiation

To investigate changes in BRCA1 following DNA damage, we exposed MCF-7 cells to increasing doses of ultraviolet C. We observed an increase in BRCA1 protein levels above 78 J/m². This increase was observed as early as 5 min after irradiation. BRCA1 levels were then observed to decrease after 2 h, consistent with the previously published data. By pretreating with cycloheximide prior to irradiation, we observed a decrease in the protein half-life, from 3.5 h to 53 min, suggesting that a decrease in protein half-life may cause the lower levels of BRCA1 after irradiation. We also observed an increase in BRCA1 mRNA within 15 min of irradiation, followed by a decrease after 4 h. These data suggest that newly translated protein may contribute to increases in BRCA1 protein levels. The very rapid changes in BRCA1 support its role as a sensor of DNA damage, as opposed to being a repair gene. Received 6 April 2000; received after revision 23 May 2000; accepted 23 May 2000     

The efficacy of a novel compound, (E)-1-(4′-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene againstTrypanosoma cruzi in mice

Summary The biological properties of a novel compound 353C with high activity againstTrypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C had a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.