Antioxidant properties of thiamine.

Thiamine (10(-4)-10(-6)M) inhibits lipid peroxidation in rat liver microsomes and free radical oxidation of oleic acid in vitro. Thiamine interacts with free radicals and hydroperoxides and is oxidized to thiochrome and thiamine disulfide. The antioxidant effect of thiamine is probably related to successive transfer of 2H(+)from the NH(2)group of the pyrimidine ring and H(+)from the thiazole ring (after its opening) to reactive substrates.

Participation of peroxidase reaction in thiamine catabolism.

The horse-radish peroxidase catalyzes oxidation of thiamine in vitro in presence of hydroperoxide hydrogen (H2O2) and olenic acid (LOOH) (as an emultion) with formation of thiochrome (2,7-dimethyl-8-(oxyetyl-5,6-dihydrothiazolo (2,3-a) pyrimido (4,5-d) pyrimidine, oxodihydrothiochrome (2,7dimethyl-oxo-8-(-2-oxo-ethyl)-5,6,9a, 10-tetrahydrothiazolo (2,3-a) pyrimido (4,5-d) pyrimidine and thiamine disulfide (bis (3-methyl-((1-methyl-4-amino 5 pyrimidine methylformyl) amino 1-2 (oxyethyl)-1-propenyl) disulfide. The transformation of thiamine to thiochrome cause by release of two atoms of hydrogen from NH2-group of pyrimidine ring of molecule of thiamine and occurrence on this place of bond with thiozole ring. The microsomal fraction of rats in vitro in presence of LOOH also activities the oxidation of thiamine to thiochrome.

[Correction of disorders in the monooxygenase system function with diethylnicotinamide (cordiamine) in tetrachloromethane- induced and viral hepatitis].

Content of cytochromes P-450 and b5 and the rate of oxidative dealkylation in liver microsomes as well as the antipyrine pharmacokinetics were normalized in rats with acute CCl4-induced hepatitis after treatment with cordiamine (diethyl nicotinamide) at a dose of 40 mg, subcutaneously, 2 times daily within 4 days. Cordiamine (30 drops 3 times daily within 8 days) contributed to normalization of the hydroxylating reaction in liver tissue of patients with viral hepatitis A, estimated by the "antipyrine" test. The drug exhibited stabilizing effect on hydrophobic interactions in microsomal membranes; diethyl nicotinamide possessed antiradical and vitamin properties.

[The effect of methotrexate on phenobarbital induction of monooxygenases and UDP-glucuronyltransferases in rat liver].

Methotrexate (N10-methyl-4-amino-4-deoxyfolic acid), administered to rats subcutaneously at a dose of 0.25 mg/kg within 14 days, was found to decrease content of microsomal protein in liver tissue and content of cytochromes P-450 and b5 as well as the drug decreased activity of amidopyrine- and ethylmorphine-N-demethylases, aniline-p-hydroxylase, UDP-glucuronosyltransferase and urinary excretion of glucuronides by 21%, 60%, 39%, 33%, 53%, 21%, 41% and 28%, respectively. Phenobarbital, administered subcutaneously at a dose of 60 mg/kg within 14 days, elevated the parameters by 28%, 187%, 63%, 163%, 162%, 100%, 95% and 60%, respectively.

[Diethylnicotinamid (cordiamine) stabilization of the liver hydroxylating function in rabbits with CCl4 poisoning].

Three and ten days after the administration of CCl4 (subcutaneously, once, 4 ml/kg of 50% oil solution) there were found a decrease of the rate of antipyrine elimination (intravenously, 50 mg/kg) from the blood plasma, an increase of the total bilirubin content, ALT activity and stimulation of lipid peroxidation processes. Cordiamine administration (subcutaneously, twice a day, 3 and 10 days) exerts the normalizing effect.

[A comparative study of the effects of nicotinamide and diethylnicotinamid on hepatic monooxygenase, glucuronyl and glutathione conjugating systems].

The nicotinamide administration to rats (50 mg/kg, subcutaneously, over 5 days) increased the concentration of liver cytochrome b5, the activities of cytosol and microsomal glutathione S-transferase, UDP-glucuronosyltransferase and urinary excretion of bound glucuronic acid by 26.7, 33.1, 33.

[Changes in UDP-glucuronosyl-, glutathione-S-transferase and lipid peroxidation in rat liver microsomes during gamma-irradiation and protective effect of alpha-tocopherol].

Stimulation of lipid peroxidation, accompanied by a decrease in activity of UDP-glucuronyl- and glutathione-S-transferases, was observed in rat liver microsomes within one day after gamma-irradiation. Maximal alteration of the patterns studied was detected within 5 days. Preadministration of alpha-tocopherol, within 14 days at a dose of 200 mg/kg of body mass, prevented distinctly the impairing effect of irradiation.

[The effect of diethylnicotinamide (cordiamine) on the activity of the hydroxylating and glucuronyl-conjugating systems in humans].

Administration of diethylnicotinamide (250 mg orally three times for 8 days) to healthy subjects increased antipyrine (AP) elimination from the saliva by 23% and decreased its half-life by 26%. The excretion in the urine of the products of AP hydroxylation 3-carboxymethylantipyrine and nor-antipyrine as well as glucuronides 3-hydroxymethylantipyrine increased. A positive correlation between the dynamics of the excretion of antipyrine metabolites and glucuronic acid was observed.

[The effect of folic acid and methotrexate on the activity of the glucuronyl- and glutathione-conjugating systems of the liver in rats].

Administration to intact male rats of folic acid (25 mg/kg intragastrically for 14 days) was shown to increase and that of methotrexate (0.5 mg/kg subcutaneously) for 14 days) to decrease the activities of the rat liver uridine-diphosphate-glucuronosyl- and glutathione-S-transferases.

[Effect of the diethylamide of nicotinic acid (cordiamine) on the hydroxylating function of the liver].

Diethylamide of nicotinic acid (subcutaneously, 40 and 120 mg/kg, once a day for 4 days) was shown to exert no influence on p-hydroxylation of aniline and to increase the rate of N-demethylation of amidopyrine and ethylmorphine in the rat liver microsomal fraction by 21 and 47% as compared with the control. At the same dose of 40 mg/kg and the same schedule of administration the drug was found to increase urine excretion of antipyrine metabolites: nor-antipyrine, 4-hydroxy-antipyrine and the sum of metabolites by 229, 89 and 80%, respectively, during the first 90 min of the experiment. Excretion of antipyrine, 3-hydroxymethyl-antipyrine and 3-carboxymethyl-antipyrine underwent no significant changes.

[Evaluation of liver monooxygenase function by the kinetics of antipyrine and its metabolites in liquid media of the body].

The presented findings indicate that the determination in the blood or saliva of antipyrine concentration kinetics as well as the profile and the ratio of the products of its hydroxylation in the urine makes it possible to evaluate under clinical conditions the activity of the hydroxylating (monooxygenase) system of the human liver and, consequently, the state of its main therapeutic-metabolizing function that is undoubtedly important for the optimization of pharmacotherapy.

[Effect of nicotinamide on lipid peroxidation].

Nicotinamide (10-100 mM) caused a decrease in total "fast" flash of chemoluminescence, in rates of NADPH- and ascorbate dependent lipid peroxidation in microsomal fraction of rat liver tissue. Content of cytochrome P-450 (carbonyl complex) as well as rates of amidopyrine N-demethylation and aniline p-hydroxylation were also decreased in microsomal fraction. At the same time, inhibition of chemoluminescence was found after addition of 50, 100 mM nicotinamide to blood plasma or to solution of oxidized oleic acid.

[Effect of nicotinic acid, nicotinamide and its combination with ziksorin and phenobarbital on the UDP glucuronyl transferase activity of the hepatic endoplasmic reticulum in the rat].

Nicotinic acid and nicotinamide (100 mg/kg) increase the activity of the rat liver microsomal uridine diphosphate-glucuronyltransferase by 55 and 73.8%. Administration of nicotinamide in combination with ziksorin or phenobarbital enhanced the enzyme-inducing effects of the latter.

[Effect of folic acid on the activity of monooxygenase system, UDP-glucuronyl- and glutathione-S-transferase in the normal and regenerating rat liver].

After administration into rats of folic acid at a dose of 25 mg/kg within 14 days activities of NADPH-cytochrome P-450 and NADH-cytochrome b5 reductases, content of cytochromes P-450 and b5 as well as the rates of NADPH and NADH oxidation were increased in liver microsomes. The stimulating action of the vitamin was also observed within later periods of liver tissue regeneration during 8 days after partial hepatectomy. Content of cytochrome b5, binding of cytochrome P-450 with aniline, N-demethylation of ethylmorphine as well as activities of UDP-glucuronyl- and glutathione-S-transferases were increased by 23-46% after the treatment as compared with control partially hepatectomized animals.

[Action of substances altering the intracellular cAMP level on the enzymes of the oxidative metabolism of xenobiotics].

The substances decreasing (insulin subcutaneously 30 U/kg single dose) and increasing (isadrin, theophylline orally 30 mg/kg five times with 12-hour intervals) the intracellular level of cAMP exert varying effects of the activities of mono-oxygenases of the rat liver endoplasmic reticulum. Insulin decreases aniline binding with cytochrome P-450 and the rate of its p-hydroxylation (after 6, 12 hours), the content of cytochrome P-450 and the rate of NADP.H oxidation (after 12 hours), the rate of NAD.

[Effect of folic acid and methotrexate on the function of the hydroxylating system and the cholesterol and phospholipid content in the liver microsomes of rats].

Folic acid and its antivitamin methotrexate exert contrary actions on the activity of monooxygenases of the rat liver endoplasmatic membranes. Under the influence of folic acid (intra-abdominally, 100 mg/kg-6 days, 25 mg/k-14 days) there is a growth in the B5 and P-450 cytochrome content, NADP.H-cytochrome P-450 and NAD.

[Effect of vitamin D2 on the monooxygenase activity of the rat liver].

Stimulation of lipid peroxidation in the liver microsomal fraction and alteration in the xenobiotic metabolism were found within twelve hrs after a single vitamin D2 administration (960,000 MU/kg) into male rats. The effects observed appear to occur due to the vitamin D2 prooxidative properties.

[Interaction in vitro of nicotinamide and diethylnicotinamid (cordiamine) with enzymes of the liver microsomal hydoxylating system in the rat].

Addition of nicotinamide and diethylnicotinamide (cordiamine) to rat liver microsomes leads to the formation of an enzyme-substrate Type II complex with cytochrome P-450. Diethylnicotinamide exceeded nicotinamide approximately 2-fold as regards the degree of the affinity to the enzyme. The ability of nicotinamide and diethylnicotinamide to interact with cytochrome P-450 underlies their antagonism with respect to in-vitro metabolism of the substrates of both Type I (amidopyrine) and Type II (aniline) as well as with respect to the competition with CO for the common center of binding on the enzyme.

[Comparative study of the effect of prolonged administration of nicotinic acid, nicotinamide and diethylnicotinamid (Cordiamin) on the rat liver monooxygenase system].

Nicotinic acid (50 mg/kg), nicotinamide (50 mg/kg) administered to rats intragastrically for 45 days do not exert any effect on the activity and the content of liver microsomal monooxygenase. Diethylnicotinamide (cordiamine) given in an equimolar dose (73 mg/kg) increases the microsomal content of cytochromes P-450 and b5, activates oxidoreductase of the components of the NADP X H-dependent redox-chain of the microsomal membranes, speeds up N-demethylation of amidopyrine and p-hydroxylation of aniline.

[Protective effect of alpha-tocopherol on the hydroxylating system in liver endoplasmic reticulum membranes against the damaging activity of hyperbaric oxygenation].

Effect of hyperbaric oxygenation (oxygen pressure 3039 hPa, exposition 3 hrs) on activity of the hydroxylating system and lipid peroxidation was studied in membranes of rat liver endoplasmic reticulum. Within the first 3 hrs after hyperbaric oxygenation the rates of aniline n-hydroxylation, amidopyrine N-demethylation, NADPH oxidation and the cytochrome P-450 level were decreased, while the rates of ascorbate- and NADPH-dependent lipid peroxidation were increased. Oil emulsion of alpha-tocopherol, administered per os into rats at a dose of 50 mg/kg every 12 hrs within 2 days before hyperbaric oxygenation, prevented the posthyperoxic deterioration of xenobiotic metabolism and the intensification of lipid peroxidation in liver microsomes.