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. However in these conditions peroxidase reaction is proceeded more slowly.

[Correction of disorders in the monooxygenase system function with diethylnicotinamide (cordiamine) in tetrachloromethane- induced and viral hepatitis]. / Korrektsiia diétilnikotinamidom (kordiaminom) narusheniia funktsii monooksigenaznoi sistemy pri tetrakhlormetanovom i virusnom gepatitakh.

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]. / Vliianie metotreksata na fenobarbitalovuiu induktsiiu monoksigenaz i UDF-gliukuronoziltransferazy pecheni krys.

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. The effect of phenobarbital in combination with methotrexate was decreased by 77%, 49%, 55%, 52%, 43%, 42% and 22%, respectively.

[Diethylnicotinamid (cordiamine) stabilization of the liver hydroxylating function in rabbits with CCl4 poisoning]. / Stabilizatsiia diétilnikotinamidom (kordiaminom) gidroksiliruiushchei funktsii pecheni krolikov pri otravlenii CCl4.

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]. / Sravnitel'noe izuchenie vliianiia nikotinamida i diétilnikotinamida na monooksigenaznuiu, gliukuronil- i glutationkon"iugiruiushchuiu sistemy pecheni.

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, 33.3, 53.0 and 31.0%, respectively. The chloral hydrate-induced sleep time in mice was reduced by 65%. Under similar experimental conditions the administration of equimolar amounts of diethylamide of nicotinic acid (75 mg/kg) exerted a more pronounced enzyme-stimulating effect. The cytochrome P-450 concentration, the activities of cytosol and microsomal glutathione S-transferase, UDP-glucuronosyltransferase as well as the sulphobromophthalein elimination from blood plasma and urinary excretion of bound glucuronic acid were increased by 37.0, 33.1, 54.6, 80.5, 24.5 and 49.0%, whereas the chloral hydrate-induced sleep time decreased by 75%. The nicotinamide and diethylamide of nicotinic acid stimulating effects on xenobiotic biotransformation in rat liver are assumed to be due to enhanced NADPH, glutathione and UDP-glucuronic acid biosynthesis as well as their antioxidant properties.

[Changes in UDP-glucuronosyl-, glutathione-S-transferase and lipid peroxidation in rat liver microsomes during gamma-irradiation and protective effect of alpha-tocopherol]. / Izmenenie aktivnosti UDP-gliukuronozil-, gliutation-S-transferaz i perewkisnogo okisleniia lipidov mikrosom pecheni krys pri gamma-obluchenii i zashchitnoe deistvie alpha-tokoferola.

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]. / Vliianie diétilnikotinamida (kordiamina) na aktivnost' gidroksiliruiushchei i gliukuronilkon''iugiruiushchei sistem u liudei.

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 elimination from blood of bilirubin glucuronides increased. Diethylnicotinamide in therapeutic doses is supposed to stimulate the processes of hydroxylation and glucuronyl conjugation in humans.

[The effect of folic acid and methotrexate on the activity of the glucuronyl- and glutathione-conjugating systems of the liver in rats]. / Vliianie folievoi kisloty i metotreksata na aktivnost' gliukuronil- i glutationkon''giruiushchikh sistem pecheni krys.

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]. / K voprosu o vliianii diétilamida nikotinovoi kisloty (kordiamina) na gidroksiliruiushchuiu funktsiiu pecheni.

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. The duration of hexobarbital-induced sleep of the rats was shown to be decreased by 26%.

[Evaluation of liver monooxygenase function by the kinetics of antipyrine and its metabolites in liquid media of the body]. / Otsenka monooksigenaznoi funktsii pecheni po kinetike antipirina i ego metabolitov v zhidkikh sredakh organizma.

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 nicotinic acid, nicotinamide and its combination with ziksorin and phenobarbital on the UDP glucuronyl transferase activity of the hepatic endoplasmic reticulum in the rat]. / Vliianie nikotinovoi kisloty, nikotinamida i ego kombinatsii s ziksorinom i fenobarbitalom na aktivnost' UDF-gliukuroniltransferazy éndoplazmaticheskogo retikuluma pecheni krys.

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 nicotinamide on lipid peroxidation]. / Vliianie nikotinamida na protsessy perekisnogo okisleniia lipidov.

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. With an increase in nicotinamide concentration its inhibitory effect on lipid peroxidation was more distinct.

[Effect of folic acid on the activity of monooxygenase system, UDP-glucuronyl- and glutathione-S-transferase in the normal and regenerating rat liver]. / Vliianie folievoi kisloty na aktivnost' monooksigenaznoi sistemy, UDF-gliukuronil- i glutation-S-transferaz normal'noi i regeneriruiushchei pecheni krys.

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. At the period of high mitotic activity of hepatocytes, within 2 days after the operation, the vitamin did not affect the parameters studied.

[Action of substances altering the intracellular cAMP level on the enzymes of the oxidative metabolism of xenobiotics]. / Deistvie veshchestv, izmeniaiushchikh vnutrikletochnyi uroven' tsAMF, na fermenty okislitel'nogo metabolizma ksenobiotikov.

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.H oxidation (after 24 hours). The activity of NADP.H-nitrotetrazolium reductase, content of cytochrome B5, the rate of aniline p-hydroxylation are increased by theophylline, and the rate of NADP.H and NAD.H oxidation and the content of cytochrome P-450 are increased by theophylline and isadrin.