Comparison between Fractional Turnover Rate of Endogenous Plasma Triglycerides and of Intralipid® (Intravenous Fat Tolerance Test) in Man*

Abstract. The validity of the intravenous fat tolerance test (IVFTT) as a tracer for the fractional turnover rate of endogenous plasma triglycerides (TG) has been studied in 32 fasting men with either normal or elevated plasma TG concentrations. The endogenous plasma TG turnover was determined by sampling arterial and hepatic vein blood, determination of splanchnic net secretion of plasma TG and calculation of fractional TG turnover rate. Later the fractional elimination rate of exogenous TG was determined following a single IV injection of Intralipid® (IVFTT). The TG fractional removal rate constants derived from these two tests were significantly correlated (r= 0. & -0.7) but IVFTT gave higher absolute values. A statistical evaluation showed that the error for the determination of the fractional turnover rate of endogenous TG and the IVFTT were about 30–50% and 10% respectively. It is probable that the correlation would have been still better if the error for the estimation of endogenous plasma TG turnover had been lower. A significant negative correlation was found between very low density lipoprotein-TG concentration and fractional removal rate of both endogenous and exogenous plasma TG (r=?0.7–0.8).     

Influence of alterations in drug metabolism on spontaneous and epinephrine-induced cardiac arrhythmias in animals exposed to trichloroethylene.

Studies were conducted to examine the effect of trichloroethylene on the cardiac rhythm and the influence of alterations in drug metabolism on the occurrence of spontaneous and epinephrine-induced arrhythmias. Rabbits and rats were treated with saline or the inducing agents, phenobarbital or Aroclor 1254, or the inhibiting agents, SKF 525A or Lilly 18947, and were exposed to trichloroethylene in an inhalation chamber under dynamic airflow conditions for 1 hr. Increasing doses of epinephrine (0.5–4 μg/kg, iv) were administered after 0, 7.5, 15, 30, 45, and 60 min of exposure until arrhythmias occurred. Rabbit controls exhibited premature ventricular beats when challenged with epinephrine (1 μg/kg) after 30 min of exposure. Serial blood samples were collected from rabbits and analyzed for trichloroethylene, trichloroethanol, and trichloroacetic acid by gas chromatography. Rabbits treated with SKF 525A or Lilly 18947 developed more arrhythmias after shorter exposure times in response to lower doses of epinephrine than controls and had higher blood concentrations of trichloroethylene. Phenobarbital-treated rabbits developed fewer arrhythmias and had lower blood concentrations of trichloroethylene. Aroclor 1254 did not alter trichloroethylene metabolism or arrhythmia development. No correlations were found between the blood concentrations of trichloroethanol and trichloroacetic acid and cardiac arrhythmias. Only those rats treated with SKF 525A developed spontaneous and epinephrine-induced arrhythmias. The data indicate that trichloroethylene can precipitate spontaneous and epinephrine-induced arrhythmias in the rat and rabbit, and the rate of metabolism of trichloroethylene can alter susceptibility to the development of these arrhythmias.     

Distribution of urethane and its binding to DNA, RNA, and protein in SENCAR and BALB/c mice following oral and dermal administration

Urethane produces threefold more skin papillomas when administered orally than dermally in SENCAR mice, a strain susceptible to tumorigenesis. To better understand the relation of distribution to the initiation stage, [14C]urethane (0.10 mg/kg, 2.5 muCi/25 g) was administered orally and dermally to male SENCAR and BALB/c mice. Absorption of urethane was greater in the first hour in SENCAR mice by both routes, as indicated by more label in the liver, lung, and stomach than found in these tissues in BALB/c mice. These differences were not observed at later time periods after oral administration. Following dermal application, higher levels were maintained in the liver, lungs, and stomach through 48 h in the SENCAR mice when compared to BALB/c mice. Binding of [14C]urethane (0.062 mg/g body weight, 20 microCi/20 g body weight) to DNA, RNA, and protein 6 h after oral administration varied with tissue (liver greater than stomach greater than skin = lung) but did not differ with strain. Binding to DNA in skin, lung, and stomach, RNA in stomach, and protein in stomach and liver after 48 h were significantly higher in SENCAR mice than in BALB/c mice. Dermal application of [14C]urethane resulted in severalfold higher binding to liver DNA of SENCAR mice than BALB/c mice, but DNA binding was comparable in other tissues after 6 h. At 48 h after dermal application, significantly higher levels of [14C]urethane remained bound to skin DNA, RNA, and protein in BALB/c mice, although all values were lower than at 6 h after treatment. Differences in the distribution and binding of urethane probably do not account for the discrepancies in tumor sensitivity. Liver DNA hydrolysates were examined after 48 h. Thin-layer chromatography showed little incorporation of the 14C into the normal deoxyribonucleotide or deoxyribonucleoside bases, and no modified bases were apparent. Radioactivity was present in the fraction that remained at the origin and was consistent with a dinucleotide fragment resistant to phosphodiesterase cleavage, such as a phosphotriester.     

Partially purified white bean amylase inhibitor reduces starch digestion in vitro and inactivates intraduodenal amylase in humans

Whether commercial, bean-derived alpha-amylase inhibitor preparations failed to decrease starch digestion in humans because of insufficient antiamylase activity, destruction by gastrointestinal secretions, or decreased activity in the presence of starch is unknown. We used a simple partial purification procedure to markedly concentrate the inhibitor (sixfold to eightfold by total protein content, and 30-40-fold by dry weight). Compared with a commercial preparation and crude bean extract, this partially purified inhibitor inactivated intraduodenal, intraileal, and salivary amylase in vitro faster and more completely (p less than 0.001); its specific activity was not affected by exposure to gastric juice and was only minimally reduced by duodenal juice. Whereas the rate of amylase inhibition by inhibitor was markedly slowed in the presence of nondietary liquid starch, dietary solid starch had only a minimal effect. Consequently, the partially purified inhibitor had no effect on liquid starch digestion, but decreased in vitro digestion of dietary starch in a dose-dependent manner (p less than 0.001). Perfusion of the partially purified inhibitor (2.0, 3.5, or 5.0 mg/ml at 5 ml/min) into the duodenum of humans rapidly inhibited greater than 94%, greater than 99%, or greater than 99.9% of intraluminal amylase activity. We conclude that commercial amylase inhibitors failed to decrease starch digestion in vivo mainly because they have insufficient antiamylase activity. However, a partially purified inhibitor with increased specific activity is stable in human gastrointestinal secretions, slows dietary starch digestion in vitro, rapidly inactivates amylase in the human intestinal lumen, and, at acceptable oral doses, may decrease intraluminal digestion of starch in humans. Such an inhibitor therefore deserves study.     

Metabolic contribution of CO2 to the "group effect"

Metabolic rates (VCO2) were determined in 22 mice. Subsequently 11 of the mice were placed into separate metabolic chambers. Each chamber was connected to one other metabolic chamber containing one mouse. The metabolic rates of the 11 "donor" and the 11 "'recipient" mice were measured. Afterwards the direction of airflow was reversed so that the previous donor became the recipient mouse and the previous recipient became the donor. Again VCO2 was measured. When the mice were donors, VCO2 = 2.75 +/- 1.0 ml CO2 . g-1 . h-1, whereas when recipients, VCO2 = 1.9 +/- 1.0 ml CO2 . g-1 . h-1 (P less than 0.01). Eleven of the mice were then made anosmic using an intranasal instillation of 5% ZnSO4. Anosmia was confirmed behaviorally. The metabolic rates of the anosmic and control mice were again determined when each was a donor and a recipient. VCO2 dropped from 3.1 to 1.8 ml CO2 . g-1 . h-1 from donor status to recipient status. Finally, VCO2 was determined when all 22 mice were exposed to 0.05% CO2 or 0.2% CO2 in air (the level of CO2 in the exhaust air of donor mice). VCO2 dropped from 3.0 +/- 0.38 on 0.05% CO2 to 1.7 +/- 1.01 on 1.01 ml CO2 . g-1 . h-1 on 0.2% CO2 in the anosmic group and from 2.9 +/- 0.29 to 1.91 +/- 0.51 ml CO2 . g-1 . h-1 in the control group when exposed to the same gases. These experiments suggest that the airborne factor emanating from the donor chambers was acting systematically and not via the olfactory system. This factor may be a low level of CO2.