Current investigations of modifications of metabolic activation of carcinogens by the environmental chemical factors which are able to induce or inhibit the metabolic activation are reviewed. From the standpoint of ecological oncology the most promising are the following trends: 1) modelling under experimental conditions of integral ecosystems including the complex of living organisms, environmental carcinogens, and factors which modify their biotransformation; 2) study of the imprinting effectors of metabolism modifiers; 3) detection in the environment of modifiers of metabolic activation of carcinogens. The comprehensive oncological-ecological studies of chemicals which influence different pathways of carcinogen metabolism are very important for both primary prevention of cancer and the environmental protection.

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.

A new inducer of the monooxygenase system zixoryn (oral dose--100 mg/kg, for 4 days) increased the excretion and maximum tubular transport of cardiotrast (diodrast) in rats. Zixoryn had no effect on daily and water diuresis and renal excretion of sodium, potassium and creatinine.

Glucocorticoids induce tyrosine aminotransferase synthesis in 7777 Morris hepatoma but fail to do so in Zajdela hepatoma. This internal property indicates the resistance to the hormone. However, both hepatoma cell lines do respond to the triamcinolone acetonide in a similar way, as judged by some other criteria, e. g. interaction with the immobilized hormone on the inert carrier, adhesion to glass and kinetic parameters of alkaline phosphodiesterase I activity. Moreover, both cell types respond to glucocorticoids by modification of synthesis of some proteins, as revealed previously by two-dimensional electrophoresis. The results show that in case of tumour cells which retain their specific receptor apparatus but do not respond to glucocorticoids by usual criteria, the conclusion whether tumour cells are hormone-sensitive or not has to be drawn from the analysis of their multiple response judging by several assays.

The P388rm and P388rx cell lines resistant to antracycline antibiotics were obtained as a result of chemotherapy of mice bearing P388 leukemia, by means of increasing dosages of rubomycin and ruboxyl, respectively. These cell lines possessed cross-resistance to vinblastine, vincristine, colchicine, actinomycin D and some other drugs. Multidrug resistance (MDR) of P388rm and P388rx is due to decreased uptake of different cytotoxic compounds by the cells. Development of resistance to rubomycin and ruboxyl was accompanied by the appearance of additional chromosomal structures--long homogeneously staining regions (HSRs), double minute chromosomes and others usually containing amplified DNA sequences. Southern blot-hybridization with cloned DNA fragments amplified in Djungarian and Chinese hamster cell lines having MDR has revealed in P388rm and P388rx cells approximately 50-fold amplification of mdr and pC52 genes. Thus, in mouse leukemia cells which acquired MDR in vivo, as a result of chemotherapy, amplification is observed of the same genes that undergo amplification during selection of cell cultures for MDR in vitro.

Using the previously obtained data on the substrate-type induction of monooxygenase by xenobiotics of phenobarbital type, the method of conversion of typical substrates for cytochrome P-450 into inducers of biosynthesis of this enzymatic system by blocking in the substrate molecule of the position subjected to oxidative conversion in the enzyme active center was tested. The introduction of the methyl group in the omega-1 position of amobarbital, of Cl- into positions 2 and 4 of biphenyl and the substitution of methyl groups for the isopropyl groups in the 4-N(CH3)2 position of aminopyrine provides for marked induction of these derivatives of cytochrome P-450 and some monooxygenase activities.

In contrast to the intact EGF, a cyanogen bromide derivative of EGF (EGF-CNBr) does not induce an increase in uridine phosphorylation rate in 3T3 cells, the ability of the EGF-CNBr to stimulate autophosphorylation of the EGF-receptor in A-431 cells being reserved. EGF and EGF-CNBr were used in concentrations promoting their equivalent binding with EGF receptor in both the series of experiments, which was necessary because of a decreased affinity to binding EGF-CNBr. Thus, the EGF-induced receptor autophosphorylation was not enough for uridine kinase activation. The differences between EGF and EGF-CNBr cellular processing made it possible to discuss potential ways of uridine-kinase activity regulation during the early period of stimulation of quiescent cell cultures.

Pectate lyase synthesis in the cells of Erwinia carotovora ELA 49 is induced by polypectate. This suggested that the Erwinia chromosomes carried a regulator gene responsible for negative regulation of the pectate lyase gene expression. In the present study the regulator gene controlling expression of one of the pectate lyase structural genes was cloned and designated as ptlA gene. For this purpose a genetic system with the tester plasmid pPc624 as the main element was constructed. The tester plasmid contained cat gene (resistance to chloramphenicol) controlled by the promotor of the ptlA gene cloned on vector pPD620. Plasmid pPC624 was maintained in the E. coli cells in a number of 1-2 copies and transferred resistance to chloramphenicol in concentrations up to 100 micrograms/ml to the cells. The E. carotovora cells containing pPC624 were sensitive to chloramphenicol in media containing no inductor (sodium polypectate). In media with the inductor they were resistant to chloramphenicol. Therefore, plasmid pPC624 proved to be a suitable system for testing the regulator gene product. The E. coli cells containing plasmid pPC624 were transformed by the hybrid Ptl+ plasmids identified in the clonotheque of the Erwinia DNA EcoRI fragments. The E. coli cotransformants were characterized by chloramphenicol sensitivity which provided a conclusion that the regulator ptlR gene controlling the ptlA gene expression was localized on the DNA EcoRI fragment (7.3 kb) containing the pectate lyase ptlA and ptlB genes. Deletion analysis showed that the investigated genes were localized in the EcoRI fragment (7.3 kb) of the E. carotovora chromosomal DNA in the following order: ptlA--ptlB--ptlR.(ABSTRACT TRUNCATED AT 250 WORDS)

The content of P-450 cytochrome and vitamin A was determined in the liver of mature male rats who received for a month daily parenteral administrations of phenobarbital solutions (Pb; 40 mg/kg), rheopyrine (a mixture of equal aliquots of amidopyrine and butadione; 200 mg/kg), amidopyrine (100 mg/kg) or water (control). The animals were kept on a semisynthetic diet, receiving once, every week 400 IU of retinol-palmitate per rat. Pb administration markedly (more than threefold) increased P-450 cytochrome content in the liver. Rheopyrine and amidopyrine also elevated its level, but to a lesser extent than Pb. Pb and rheopyrine also depressed vitamin A levels in the liver and caused either a trend towards its decrease (Pb) or a significant decrease (rheopyrine) of its overall content in the liver. The effect of amidopyrine on the concentration and storage of retinol in the liver was less pronounced. The data obtained suggest that the drugs inducing P-450 cytochrome are capable of disturbing vitamin A content in the body.

Contents of cytochrome P-450 and b5, rates of oxidation of aniline, amidopyrine and dimethylaniline as well as activities of NADP-H- and ascorbate-dependent systems of lipid peroxidation (LPO) in rat liver microsomes five months after single administration of the mixture of polychlorinated diphenyls (PCD) significantly exceeded the control level. Starvation of the animals for 120 hours led to an additional increase of cytochrome P-450 content and LPO activation. The rat liver monooxygenase system retained the ability to respond to the inducing action of the mixture of PCD (500 mg/kg) during starvation.

The influence of ascorbic acid (vitamin C) on the frequency of occurrence of colchicine- and methotrexate-resistant colonies of Djungarian hamster DM-15 cells was studied the number of resistant cells was found to increase 2.9-19.8-fold. The genetic effect of using high vitamin C doses is discussed.

Zixorine, an inducer of microsomal monoxygenases, can effectively be used for the treatment of patients with allergic dermatoses. It has been established that zixorine makes the NBT-test and the IgE content in the blood serum of these patients return to normal.

Administration of phenobarbital, benzonal and benzobamil in a dose of 1/20 of LD50 to rats was shown to be followed by phase changes in the system of microsomal oxidation of the liver--activation in the first days after administration with the subsequent (in 1-3 months) decrease of the activity. The drugs activate the specific link of immunity directed at detoxication of the administered substances: increase the level of specific antibody-forming cells in the spleen and antibodies in the peripheral blood. Benzonal and bezobamil enhance the killing activity of cells of the thymus, phenobarbital and benzonal suppress the natural cytotoxicity of cells of the spleen and peritoneal exudate.

A study of the condition and function of a multienzymatic monoxygenase system in liver microsomes of rats bearing experimental Pliss' lymphosarcoma and Zajdela's ascites hepatoma showed synthesis and function of the key enzymes of the hydroxylating microsomes of the liver being inhibited and, consequently, drug metabolism slowed down.

In is shown that administration of sovol, a mixture of polychlorinated diphenyls, in a dose of 500 mg/kg (about 1:10 LD50) induces pronounced changes in the rat liver structure, in particular, fat accumulation and diminution of RNA lump number in hepatocyte cytoplasma, alteration of nuclei, decrease in the number of hepatocytes and binuclear cells in the visual field. Structural disorders in the liver are observed during a long period (up to 5 months) and, to a certain extent, depend on the composition of the lipid component of the ration. Certain differences are recorded in the character of the morphological changes in the liver after single and repeated injections of the agent. No distinct relationship is recorded between the manifestation of hepatocyte fat infiltration and other morphological changes in the liver, and the index of microsomal cytochrome P-450 induction during sovol action.

The experiments were carried out to elucidate the effect of carboxycathepsin (CC) activity inhibition by a specific inhibitor--captopril--on plasma enzyme concentration in normotensive rats and rats with renovascular hypertension. A single oral administration of captopril (10 mg/kg body weight) produced an increase in CC concentration in both hypertensive and sodium-depleted normotensive rats with a parallel decrease in arterial pressure, but had no effect on sodium-repleted normotensive rats. It is suggested that the increase in plasma CC concentration is a compensatory response to the inhibition of CC activity by captopril; it is also possible that the increase observed reflects the state of renin-angiotensin system.

For the hepatocarcinogenesis initiation one-fold N-nitrosodiethylamine (NDENA) action upon the livers of embryos and of the 4-weeks rats, before or after partial hepatectomy was used. Phenobarbital and repeated partial hepatectomies were used as the promotive factors. The promotion effect was evaluated by the quantity and size of hyperplastic liver nodules, where gamma-glutamyltranspeptidase activity was revealed. It was determined, that NDENA-affected rat liver cells in the embryonic period or at the age of 4 weeks after single partial hepatectomy proved to be more sensitive to the action of promoters.