Synthesis, structure-activity relationships and a reaction mechanism for mutagenic N-nitroso derivatives of glycosylamines and Amadori compounds--model substances for N-nitrosated early Maillard reaction products.

A series of nine glycosylamines and an Amadori compound were synthesized, together with their N-nitroso derivatives. Their structures were established by physico-chemical and spectroscopic data and elemental analyses. The N-nitroso compounds were further characterized by denitrosation with hydrogen bromide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector. N-Nitroso derivatives of N-p-nitrophenyl/p-methylphenyl/p-carboxyphenyl pentopyranosylamines, N-p-methylphenyl-1-deoxy-D-fructosylamine (the Amadori compound) and N-3-ethylindole-D-xylopyranosylamine were shown to be direct-acting mutagens in Salmonella typhimurium TA100. The activity of some of the compounds was similar to that of N-ethyl-N-nitrosourea. Their mutagenic activity was shown to depend on the structure of the amine and the sugar moieties and to require the presence of free hydroxyl groups in the sugar. The mutagenicity of N-nitrosoglycosylamines was attributed to their hydrolysis to arenediazonium cations. The formation of these compounds was detected by azo-coupling with N-ethyl-1-naphthylamine, using spectrophotometric and mass spectrometric analyses. These data implicate arene(alkyl)diazonium cations as the ultimate mutagens of N-nitrosoglycosylamines (and possibly of N-nitroso Amadori compounds), a little-explored class of N-nitroso compounds that may be formed in vivo.

Further studies on liver glyoxalase I and glyoxalase II. Activity in mice bearing sarcoma 180 and L1210 leukemia.

Determinations were made of glyoxalase I and glyoxalase II acitivity in the liver of mice (BDF1 and DBA2 strains) bearing sarcoma 180 and L1210 leukemia in ascites form. A progressive decrease in the both glyoxalase I and glyoxalase II activities to about 40--60% of that of the control groups was observed within the developing period 8--9 days. Test results are interpreted in the light of the postulated role of this enzyme system in cell division and in the tumor development process.

Red blood cells deformability and oxidative stress in acute pancreatitis.

The aim of this study was to evaluate the RBC deformability and oxidative stress parameters during acute pancreatitis. Healthy volunteers and patients with mild or severe acute pancreatitis were evaluated. There were no changes in erythrocyte's deformability in patients with mild acute pancreatitis. In severe acute pancreatitis loss of deformability of erythrocytes was observed. Serum lipofuscin level increased both in mild and severe form of the disease. The superoxide dismutase (SOD) activity was increased in erythrocytes from mild and severe form without systemic complications and was positively correlated with erythrocyte's deformability in a severe form of acute pancreatitis. Significant positive correlation between serum total antioxidant status and deformability of erythrocytes in healthy humans and negative correlation in mild pancreatitis were found.

[Effect of low doses of lead and cadmium on glyoxalase I and glyoxalase II activities of the liver and brain of rats]. / Wplyw niskich dawek olowiu i kadmu na aktywnosc glioksalazy I i glioksalazy II w watrobie i mózgu szczurów.

The effects of low doses of lead and cadmium on the activities of glyoxalase I and glyoxalase II in liver and brain of male Wistar rats were examined. Generations P, F1 and F2 received lead acetate and cadmium acetate in drinking water. The doses were as follows: group I-Pb 5 ppm, group II-Pb 50 ppm, group III-Cd 0,1 ppm, group IV-Cd 5 ppm. group V-Pb 5 ppm + Cd 0,1 ppm, group VI-Pb 50 ppm--Cd 5 ppm. The control group received sodium acetate with water. P population received Pb and Cd for 40 days before fertilization, and then the pregnant females were given the same doses until the end of pregnancy. Animals of F1 and F2 generation were killed after 30, 60 or 90 days. In liver and brain homogenates the activities of glyoxalase enzyme system were determined by the spectrophotometric method at 240 nm. A little inhibition of glyoxalase I was observed in rats that were given lead for 30 days, while in rats treated for 60 and 90 days the activities of glyoxalase I increased. Glyoxalase II was activated both by lead and cadmium in all groups. In vitro examinations demonstrated that lead and cadmium inhibited the activity of glyoxalase I and activated glyoxalase II.

[Participation of glyoxalases and methylglyoxal in diabetic complication development]. / Udzial glioksalaz i metyloglioksalu w rozwoju powiklan cukrzycowych.

The glyoxalase system catalyses the conversion of methylglyoxal to D-lactate via intermediate S-D-lactoylgutathione. This system consists of two enzymes, glyoxalase I and glyoxalase II. A link between the development of diabetic complications and the glyoxalase system has been suggested at the genetic and metabolic level. Insulin-dependent diabetic patients without complications (retinopathy, neuropathy) had a significantly higher frequency of the glyoxalase phenotype GLO 1-1 than patients with complications. Periodic hyperglycaemia may contribute to the development of diabetic complication through methylglyoxal-mediated changes in protein solubility and aggregation characteristics.

Activity of erythrocytic glycoxalases I and II in bearers of certain neoplasms.

Activity of red cell glycoxalase I and glyoxalase II was investigated in 92 cancer-bearing subjects. This parameter was either higher or lower than in the control group consisting of blood donors, and changed in the course of disease. Its initial rise was followed by the fall.

[The role of methylglyoxal in the development of diabetic complications]. / Udzial metyloglioksalu w rozwoju powiklan cukrzycowych.

The formation of methylglyoxal is increased during hyperglycemia associated with diabetes mellitus. Enhanced methylglyoxal concentration in biological systems is associated with increased reversible and irreversible modification of protein. The chronic exposure to high methylglyoxal concentrations appears to be linked to the development of diabetic complications. Intervention with aldose reductase inhibitors or aminoguanidine, which is an efficient scavenger of methylglyoxal, in diabetes mellitus may prevent increased methylglyoxal concentration.

Does yohimbine act as a slimming drug?

Yohimbine, an alpha 2-receptor antagonist, was examined for its suitability in the treatment of obesity. Twenty female obese outpatients were subjected to a 3-week low-energy diet (1,000 kcal/day), after which they were randomly allocated according to a double-blind study protocol to two treatments: 10 subjects received 5 mg yohimbine per os 4 times a day and 10 received a placebo for 3 weeks, in addition to a low-energy diet of 1,000 kcal/day. Before inclusion in the study, as well as the end of each of the 3-week treatment periods, thermogenesis (resting and exercise energy expenditure) was assessed by indirect calorimetry; serum noradrenaline concentration was taken as an index of sympathetic system activity and serum glycerol level as an index of lipolysis. Yohimbine significantly increased the mean weight loss in patients on a low-energy diet: 3.55 +/- 0.24 kg (yohimbine) vs. 2.21 +/- 0.37 kg (placebo), P less than 0.005. With yohimbine, a steady level of effort-induced energy expenditure and sympathetic system activity was maintained. No significant effect of yohimbine on lipolysis was observed under the experimental conditions of this study. In another group of 15 obese inpatients (11 women and 4 men) the influence of 15 mg yohimbine per os vs. placebo on gastric emptying of a radiolabelled solid meal was examined in a double-blind manner with the use of a gamma camera. No significant effect of yohimbine on gastric emptying was revealed--the mean gastric transit time was 42.0 +/- 0.4 min after placebo and 41.8 +/- 0.5 min after yohimbine. The results obtained warrant further research on the applicability of alpha 2-receptor inhibitory drugs as a supplementary management in the treatment of obesity.

[Role of glyoxalases and methylglyoxal in cell proliferation and differentiation]. / Rola glioksalaz i metyloglioksalu w proliferacji i róznicowaniu komórek.

The glyoxalase system catalyses the conversion of methylglyoxal (and other 2-ketoaldehydes) to D-lactic acid via the intermediate S-D-lactoylglutathione. It comprises two enzymes, glyoxalases I and glyoxalases II, and catalytic amount to reduced glutathione. Methylglyoxal inhibits cell growth, while the glyoxalase system by breaking down methylglyoxal may act as a promoter of cell growth. Inhibitors of glyoxalases may serve as possible therapeutic agents against cancer by virtue of their ability to elevate the level of methylglyoxal in the body.

Synthesis of S-lactoyl-glutathione using glyoxalase I bound to sepharose 4B.

Glyoxalase I bound to Sepharose 4B was used for synthesis of S-lactoyl-glutathione. The bound enzyme does not lose its activity during several months storing and can be used many times for synthesis of S-lactoyl-glutathione. This reaction product can be used as a substrate for glyoxalase II without any further purification.