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Changes in Plasma Apolipoproteins Following Whole-Body Irradiation in Rabbit

Male New Zealand white rabbits were whole-body-irradiated with a linear electron accelerator at 800 rad ( LD50 in 30 days). This treatment induced a pronounced hypertriglyceridemia. The apoprotein composition of very low density lipoproteins (VLDL, d < 1.006 g/ml) and high-density lipoproteins (HDL, d = 1.063-1.21 g/ml) from irradiated rabbits was studied and compared to those of normal rabbits. Significant changes were observed in both very low density apolipoproteins and high-density apolipoproteins. (1) In the VLDL fraction from irradiated rabbits, there appeared in high proportion two apolipoproteins with electrophoretic mobility in urea/polyacrylamide gels similar to apoA-I and A-II but which were distinctly different in their apparent molecular weights, their isoelectric points, and their amino acid composition from these latter proteins. These proteins had apparent molecular weights of about 10,000. They focused into three bands with pI values of 6.1, 6.4, and 6.6. Their amino acid composition was ...

Effects of an antimitotic agent (cyclophosphamide) on plasma lipoproteins

A cyclophosphamide injection to male New Zealand white rabbits induced a pronounced hypertriglyceridemia and a hypercholesterolemia whose concentration was maximal at 16 hr. Different doses were studied. In this hyperlipemia significant changes in plasma lipoprotein fractions appeared: the very low density lipoproteins increased and the high density lipoproteins decreased. Lipid composition showed that HDL cholesterol was very low comparatively to a high VLDL cholesterol. The apoprotein composition of VLDL from treated rabbits was studied and compared to that of normal rabbits. After electrophoresis in urea/polyacrylamide gels, two new apoproteins which resembled those observed in irradiated rabbits appeared. The molecular weight of these proteins was about 10,000, and they focused into three bands with isoelectric points of 6.72, 6.42 and 6.10. Total lipoprotein lipase activity in treated rabbits decreased; it was very low with 32.5 mg/kg. This lipolytic activity remains to be studied after separation of hepatic triacylglycerol lipase and lipoprotein lipase activities by chromatography.

Cholesteryl ester transfer protein: Size of the functional unit determined by radiation inactivation

Radiation inactivation was used to determine the functional M r of cholesteryl ester transfer protein (CETP) in rabbit plasma from control and irradiated animals. This technique reveals the size of the functional unit required to carry out the transfer function. The functional M r was calculated to be 70000 ± 3000 (mean ± SD) for both control and irradiated rabbits. This result is in. accordance with the M r obtained by a completely different method, namely SDS‐polyacrylamide gel electrophoresis of a partially purified (110‐fold) rabbit CETP. The pI of this CETP was found by isoelectric focusing to be equal to 5.95. The results suggest that the functional unit of this enzyme is the monomer.

Triacylglycerol increase in plasma very low density lipoproteins in cyclophosphamide-treated rabbit: Relationship with cholesteryl ester transfer activity

We have studied the cholesteryl ester transfer between HDL and VLDL in cyclophosphamide-treated rabbits, in order to explain the abnormal cholesteryl ester partition between these two lipoprotein classes. The hypertriglyceridemia caused by treatment with the drug was associated with cholesteryl ester- and triacylglycerol-rich VLDL and with HDL poor in esterified cholesterol but relatively enriched in triacylglycerol. These two lipoprotein classes were characterized by their chemical composition and by gel filtration chromatography. VLDL particles were slightly larger in size, compared with controls. Different transfer combinations were envisaged between these abnormal lipoproteins and control ones. The transfer study involved the plasma fraction of d greater than 1.21 g/ml containing the cholesteryl ester transfer protein (CETP). It appeared that the chemical composition of lipoproteins was responsible for the level of cholesteryl ester transfer between lipoproteins. Actually, when the cholesteryl ester acceptor lipoproteins (VLDL) were enriched in triacylglycerol, the transfer was enhanced. Therefore, the effect of lipolysis on the transfer has also been explored. Lipoprotein lipase seemed to enhance the transfer of cholesteryl ester from HDL to VLDL when these lipoproteins were normal, but an important decline was obtained when triacylglycerol-rich VLDL were lipolyzed. This study defines the relationship between lipoprotein chemical composition and transfer activity of cholesteryl ester from HDL to VLDL.

Irradiation-induced free cholesterol accumulation in very-low-density lipoproteins. Role of lipoprotein lipase deficiency

Irradiation of rabbits induced an accumulation of free cholesterol in VLDL fraction. In the present study, an attempt was made to explain the abnormal free cholesterol enhancement. The study demonstrated that lecithin:cholesterol acyltransferase activity was normal in irradiated rabbits. In addition, electron microscopy examination of HDL revealed no changes after irradiation: spherical particles were present. On the other hand, ACAT activity was increased while neutral and acidic cholesteryl esterases were strongly decreased. Moreover, HMG-CoA reductase was 3-fold reduced after irradiation. These results show that neither cholesterol esterification nor cholesterol ester hydrolysis nor cholesterol biosynthesis are responsible for this increase of free cholesterol in VLDL. In contrast, we have shown that extra-hepatic lipoprotein lipase was deficient in irradiated rabbit plasma although synthesis in the adipocytes is normal. To investigate a hypothetical deficiency of VLDL catabolism, we performed experiments with injection of heparin and with labeled VLDL. These experiments show that, in irradiated rabbits, VLDL were not catabolized, since the radioactivity was recovered only in the VLDL fraction. This impaired VLDL removal was compatible with the deficiency of extra-hepatic lipoprotein lipase activity.

Effects of threonine-poor apolipoproteins on post-heparin plasma hepatic triacylglycerol lipase and lipoprotein lipase

Whole-irradiated rabbit pre-heparin plasma had an important inhibitory effect on hepatic triacylglycerol lipase and lipoprotein lipase activities, whereas control rabbit pre-heparin plasma slightly inhibited hepatic triacylglycerol lipase activity at a high concentration and enhanced lipoprotein lipase activity. As some apolipoproteins were known to modulate these two lipolytic enzymes, the inhibitory effects of irradiated rabbit plasma were investigated in apolipoproteins. Three apolipoproteins, with isoelectric points of about 6.58, 6.44 and 6.12, characterized by their low content in threonine (threonine-poor apolipoproteins) were produced in high concentrations in rabbit VLDL and HDL after irradiation. The effects of these apolipoproteins on control rabbit post-heparin plasma hepatic triacylglycerol lipase and extrahepatic lipoprotein lipase were studied. Threonine-poor apolipoproteins substantially inhibited the hepatic triacylglycerol lipase activity and enhanced the apolipoprotein C-II-stimulated activity of lipoprotein lipase. The amounts of these apolipoproteins in triacylglycerol-rich lipoprotein particles may determine the lipolytic activity of lipoprotein lipase and hepatic triacylglycerol lipase in triacylglycerol hydrolysis. The existence of another inhibitor of lipoprotein lipase remains to be determined.

PHARMACOKINETICS OF HIGH-DOSE IV ALIZAPRIDE IN PREVENTION OF CISPLATIN-INDUCED EMESIS

Summary— Alizapride is a new antidopaminergic‐related benzamide with specific antiemetic properties. Pharmacokinetics at a high repetitive dose (16 mg/kg) shows a biexponential plasma decay with T1/2α of 8.33 ± 2.47 min and T1/2β 2.8 ± 0.7 hr. Large Vdss and high total body clearance are apparent. We demonstrate an increase in drug exposure during the first 6 hr after CDDP infusion by shortening the interval between injections. We conclude that the rate of infusion of alizapride could be important in the efficacy of the drug.

Biodistribution study of 99m Tc labeled low density lipoprotein in B16 melanoma bearing mice. Visualization of a differential fixation in tumoral tissue

The research was focused upon the availability of lipoprotein labeled with 99mTc, tracer used in nuclear medicine, in order efficaciously to reach tumoral cells, in the present case the B16 melanoma in CD57 black female mice. In a biodistribution study, we used the parallel methods of scintigraphic images and tissue radioactivity counts of different organs.