[The role of UDP glucuronosyl- and sulfotransferases in the butylhydroxytoluene suppression of the mutagenic action of carcinogenic nitroso compounds and cyclophosphane]. / O roli UDF-gliukoronozil- i sul'fotransferaz v podavlenii butilgidroksitoluolom mutagennogo deistviia kantserogennykh nitrozosoedinenii i tsiklofosfana.

Treatment with butylated hydroxytoluene (BHT) was shown to stimulate the activity of UDP-glucuronosyltransferase and to inhibit that of sulfotransferase in liver of Wistar male rats. Addition of UDP-glucuronic acid to incubation medium in Ames' test using BHT-pretreated subfractions of rat liver resulted in decreased mutagenicity of nitrosodiethylamine, nitrosomorpholine and cyclophosphamide. Further treatment with 3'-phosphoadenosine-5'-phosphosulfate failed to affect mutagenic activity of the promutagens tested. However, an increase in mutagenicity of nitrosomorpholine and cyclophosphamide was observed in application of liver subfractions from intact animals. It was concluded that BHT-induced inhibition of active metabolite production as well as increased production of their glucuronides are responsible for inhibition of mutagenicity of the agents tested. Simultaneous decrease in the yield of sulfates potentiated this effect for nitrosomorpholine and cyclophosphamide.

[Ames test study of the effect of 2nd-phase biotransformation reactions on the level of mutagenic action of a number of chemical compounds]. / Issledovanie v teste Eimsa vliianiia reaktsii vtoroi fazy biotransformatsii na uroven' mutagennogo deistviia riada khimicheskikh soedinenii.

Introduction of cosubstrates for reactions of conjugation with the reduced glutathione, glucuronic acid and sulphate is shown to modify (increase or decrease) the level of mutagenic effect of thiophosphamide, nitrosomethylurea and DDDTDP on S. typhimurium TA 1950 or TA 1534.

[Additional pathway of the metabolic activation of N-nitrosodiethylamine in the rat liver]. / Dopolnitel'nyi put' metabolicheskoi aktivatsii N-nitrozodiétilaminav pecheni krys.

A cytosolic enzyme, aldehyde oxidase (AO), was shown to be involved in metabolic activation of carcinogenic diethylamine (DENA). DENA was reduced to corresponding hydrazines by AO in the presence of benzaldehyde. Products of DENA reduction by AO possessed mutagenic activity for Salmonella typhimurium TA 1950. Pretreatment of rats by antioxidant butylhydroxytoluene had no effect on this process of DNA bioactivation.

[Effect of modifiers of the cytochrome P-450-dependent enzyme system of the liver on the metabolic pathways of diethylnitrosamine activation and inactivation]. / Vliianie modifikatorov tsitokhrom P-450-zavisimoi fermentnoi sistemy pecheni na metabolicheskie puti aktivatsii i inaktivatsii diétilnitrozamina.

Pretreatment of Wistar male rats with antioxidants prevented the toxic effect of diethylnitrosamine (DENA) at LD50. Six-fold acceleration of DENA excretion and significant increase of maximum plasma concentration of a DENA metabolite nitrite were, also observed after antioxidants treatment. Liver microsomal metabolism of DNA was altered by pretreatment with another antioxidant--butylhydroxytoluene, which stimulated selectively denitrosation and inhibited dealkylation of DENA in the microsomal cytochrome P-450-dependent enzyme system. Moreover, butylhydroxytoluene treatment diminished he ability of microsomes to activate DENA to mutagenic intermediates identified in Ames' test. It was suggested that the protective effect of antioxidants against DENA toxicity may be due to the acceleration of its metabolic inactivation and the inhibition of its activation in liver cytochrome P-450-dependent systems.

[Butylhydroxytoluene inhibition of the mutagenic activity of carcinogenic nitroso compounds and cyclophosphamide: the role of the glutathione conjugation reaction]. / Podavlenie butilgidroksitoluolom mutagennogo deistviia kantserogennykh nitrozosoedinenii i tsiklofosfana: rol' reaktsii kon''iugatsii s glutationom.

Mutagenic effect of diethylnitrosamine, nitrosomorpholine and cyclophosphamide were studied on Salmonella typhimurium in the Ames test using S9, microsomal and cytosolic subfractions of Wistar male rats. Pretreatment with butylhydroxytoluene (BHT) was followed by a 50-60% decrease in metabolic activation of the said promutagens by liver subfractions. This was matched by an increase in cytosolic and microsomal glutathione-S-transferase activity and glutathione level in rat liver. The addition of glutathione to the incubation medium in the Ames test using liver subfractions of BHT-treated rats brought on a complete inhibition of mutagenic effect of the agents studied. It is suggested that BHT-induced decrease in production of active metabolites and increase in their inactivation in reactions of glutathione enzymatic conjugation account for the inhibition of mutagenicity of the promutagens under study.

[Study of promutagen biotransformation in the Ames test. III. The role of conjugation with glucuronic acid and sulfate in the modification of mutagenic effect of nitrosomorpholine, diethylnitrosamine and cyclophosphamide]. / Issledovanie protsessov biotransformatsii promutagenov s pomoshch'iu testa Eimsa. Soobshchenie III. O roli kon''iugatsii s gliukuronovoi kislotoi i sul'fatom v modifikatsii mutagennogo deistviia nitrozomorfolina, diétilnitrozamina i tsiklofosfana.

The role of reactions of conjugation with uridine diphosphoglucuronic acid (UDPGA) and with 3-phosphoadenosine-5-phosphosulfate (PAPS) in modification of the mutagenic effect of diethyl nitrosamine (DENA), nitrosomorpholine (NM) and cyclophosphane (CP) was studied by the Ames test. It was shown that adding UDPGA to the activating mixture significantly decreased the level of the mutagenic effect of DENA, NM and CP on bacteria Salmonella typhimurium TA 1950, when S9 and microsomal fractions of rat liver homogenate were used. Adding PAPS to the activating mixture when S9 and cytosole fractions were used, did not affect mutagenic action of DENA on S. typhimurium TA 1950 and TA 1535, enhancing the mutagenic effect of CP on TA 1535, with no such influence on TA 1950. Introduction of PAPS into the activating mixture elevated the mutagenic effect of NM on both bacterial strains using S9 fraction but not cytosole fraction.

[Study of promutagen biotransformation in the Ames test. IV. The effect of transplanted tumors on the biotransformation of various antineoplastic agents]. / Issledovanie protsessov biotransformatsii promutagenov s pomoshch'iu testa Eimsa. Soobshchenie IV. Vliianie perevivaemykh opukholei na protsessy biotransformatsii nekotorykh protivoopukholevykh preparatov.

The effect of transplantation of rat tumours Jensen sarcoma, sarcoma 45, sarcoma M-1, as well as of inoculation of rat normal connective tissue on the processes of biotransformation of antitumour preparations cyclophosphane (CP), thiophosphamide, prospidine and of model compound nitrosomorpholine (NM) was studied. The study was accomplished by means of the Ames test with indicator bacterial strain Salmonella typhimurium TA 1950 in relation to the reactions of the 1st and the 2nd phases of xenobiotics metabolism. It was shown that the presence of tumours leads to inhibition of both metabolic activation processes of the promutagens NM and CP and the conjugation reactions of genetically active metabolites of these compounds with reduced glutathione. Genetic danger is supposed to be increased during application of antitumour preparations, the mutagenic activity of which is due to the activity of their metabolites. It is noted that the most essential effect on biotransformation processes of NM and CP was exhibited by sarcoma M-1, the most important changes of the biotransformation processes of promutagens being observed in the initial period of pathologic process, i.e. on the 3rd day after inoculation. Transplantation of the normal connective tissue of rats had no effect on reactions of both the 1st and the 2nd phase of metabolism of the promutagens studied.

[The process of promutagen biotransformation studied by the Ames test. II. The extent of the manifestation of the mutagenic action of nitrosomorpholine, diethylnitrosamine and cyclophosphane using various subfractions of rat liver homogenate]. / Issledovanie protsessa biotransformatsii promutagenov s pomoshch'iu testa Eimsa. Soobshchenie II. Vyrazhennost' mutagennogo deistviia nitrozomorfolina, diétilnitrozamina i tsiklofosfana pri ispol'zovanii razlichnykh subfraktsii gomogenata pecheni krysy.

The data are presented on involvement of components of microsomal and cytosolic subfractions composing the S-9 fraction of rat liver homogenate in processes leading to formation of active metabolites of nitrosomorpholine (NM), diethyl nitrosoamine (DENA) and cyclophosphane (CP) promutagens and their detoxication resulting from the reaction with glutathione (G-SH) added to the system. It is established that the process of metabolic activation is only connected with microsomal subfraction, while reactions of the first phase of CP and DENA metabolism take place when both microsomal and cytosolic subfractions are added. Decrease in the effect of all promutagens studied under the action of G-SH was observed after microsomal and cytosolic subfractions of the S-9 fraction were introduced into the activating mixture. Various values of dependence of the metabolic activation level and the extent of decrease in the mutagenic action, upon addition of G-SH, on the protein content in microsomal and cytosolic subfractions were obtained.

[Study of the process of promutagen biotransformation by the Ames test. I. The role of conjugation with glutathione in the modification of the mutagenic activity of nitrosomorpholine, diethylnitrosamine and cyclophosphamide]. / Issledovanie protsessov biotransformatsii promutagenov s pomoshch'iu testa Eimsa. Soobshchenie I. O roli kon''iugatsii s gliutationom v modifikatsii mutagennogo deistviia nitrozomorfolina, diétilnitrozamina i tsiklofosfana.

It is demonstrated that the level of the action of nitrosomorpholine (NM), diethyl nitrosoamine (DENA) and cyclophosphane (CP) promutagens on bacteria is lowered as a result of the Ames test modification by means of addition of reduced glutathione (G-SH) to the activating mixture. The data are presented on the dependence of this phenomenon on concentration of promutagens and G-SH, the period of bacteria preincubation with the compound under study and the activating mixture as well as on concentration of microsomal protein. No changes in the mutagenic effect of NM, DENA and CP were observed when G-SH was substituted for cysteine in equimolar concentration. This fact points to enzymic mechanism involved in elimination of the damaging effect of mutagenic metabolites of the compounds studied.