[Prevalence of mutations BRCA1 5382insC, and CHEK2 1100delC in the population of Siberian region].

Frequencies of the 538insC mutation in the BRCA1 gene and the 1100delC mutation in the CHEK2 gene were compared in the group of breast cancer patients and the large-scale sample, consisting of 7920 DNA specimens from healthy residents of the city of Novosibirsk. Higher frequencies of these mutations in the patient group compared to the control sample (1.95 versus 0.25% for BRCA1 5382insC, and 1.78 versus 0.40% for CHEK2 1100delC) were observed, pointing to their association with susceptibility to breast cancer (OR = = 7.86, 95% CI 3.51-17.30 and OR =4.46, 95% C1 2.04-9.49, respectively).

[Detection of 5382insC mutation in human BRCA1 gene using fluorescent labeled oligonucleotides].

Analysis of genetic predisposition to cancer can provide valuable information for early cancer detection or even prevention. Insertion 5382insC in BRCA1 gene is the most frequent mutation among those associated with high risk of breast cancer in women of East European origin. The method of 5382insC detection using fluorescent labeled allele specific oligonucleotides in Duplex Scorpion format has been developed. The method can be used in real-time PCR conditions as well as in conditions of end-point fluorescence measurement followed regular PCR. The adequacy of the method was demonstrated in the study of 5382insC mutation frequency in breast cancer patients. 564 samples of genomic DNA from breast cancer patients were genotyped. Eleven patients (1.95%) were found to be heterozygous for BRCA1 5382insC mutation. 5382insC allele frequency in breast cancer patients group was 0.0098. The method can be used as in clinical practice to determine individuals of a high risk of breast cancer, as in wide-scale population studies.

[Frequency of the 735G --> A mutation of the 5'-splice donor site of intron 14 of the dihydropyrimidine dehydrogenase gene (DPYD) in residents of Novosibirsk region (Russia) as revealed with fluorescent oligonucleotides].

A simple method was developed for end-point fluorescence detection of the 735G --> A mutation of the 5'-splice donor site of intron 14 of the dihidropyrimidine dehydrogenase gene (DPYD). The method was based on allele-specific PCR with duplex Scorpion primers. The genotyping results obtained by the fluorescent endpoint PCR technique completely coincided with the results obtained by allele-specific PCR with amplicon detection in agarose gel. Genotyping was performed in 291 DNA samples from residents of Novosibirsk region (Russia), and two heterozygotes (0.69%) were detected.

Genetic polymorphisms of CYP1A1, GSTM1 and P53 genes in a unique Siberian population of Tundra Nentsi and its pharmacogenetic importance.

Complete data on the polymorphisms of CYP1A1, GSTM1 and p53 genes in Tundra Nentsi population, with known genealogical history are essential for the analysis of the "cancer susceptibility gene markers" distribution among different Oriental populations. The cytochrome P4501A subfamily is known to be responsible for the metabolic activation of aromatic compounds occurring in the products of gas mixture combustion, the main environmental pollutants in the north of western Siberia. Recently a close correlation was reported between development of some types of cancer and polymorphisms of human CYP1A1, GSTM1 and p53 genes. The frequency of the CYP1A1 Vol allele in the healthy part of the Tundra Nentsi population differs from those previously reported for Japanese and is more than 1.5 times higher. It is necessary to underline that homozygote Val genotype was present in 26% of non-healthy Tundra Nentsi, the incidence being 2.7-times higher in comparison with healthy population. GSTM1 gene deletion is present in 40% of Orientals and in 39% of Tundra Nentsi. Moreover, the share of individuals with null genotype among a group with chromosomal abnormalities and cancer was 63%, or 1.5 fold higher. Thus the prevalence of two polymorphic genes CYP1A1 and GSTM1 responsible for the biotransformation of polycyclic aromatic hydrocarbons was too high in the non-healthy group.

[Genetic polymorphism in glutathione S-transferase M1 and T1 in children with bronchial asthma]. / Geneticheskii polimorfizm glutation-S-transferazy M1 i T1 u detei, bol'nykh bronkhial'noi astmoi.

Asthmatic (n = 100) and health (n = 104) children were compared for rates of homozygous deletions of the glutathione S-transferase class mu and theta genes (null genotypes, GSTM1"-" and GSTT1"-", respectively). The frequency of GSTM1"-" and GSTT1"-" genotypes in patients with bronchial asthma (BA) (52 [symbol: see text] 26%) were increased compared to healthy children (42 and 11%) (odds ratio (OR) for GSTM1"-" = 1.48; CI: 0.82-2.67; p = 0.16; OR for GSTT1"-" = 2.69; CI: 1.2-6.11; p = 0.0079). OR for GSTM1"-" and GSTT1"-"-combination was 5,12; CI: 0.55-119.5; p = 0.107. We conclude that null-genotypes are associated with susceptibility to BA in children. Passive smoking (PS) increased risk of BA for children with GSTM1"-" genotype, but not with GSTT1"-" genotype. The association of these genotypes was estimated with such clinical peculiarities of BA as polyvalent allergy, early development and heavy course. In the group of nonsmoking (NS) patients was found the statistically in significant association of individual null genotypes with any clinical peculiarities. Combination of null-genotypes in NS patients associated with early development of BA (OR = 6.5; CI: 0.78-64.95; p < 0.05), and combination of plus genotypes--with polyvalent allergy (OR = 7.35; CI: 1.07-63.44; p < 0.05). In the group of PS patients GSTM1"-" genotype was associated with early development of BA (OR = 9.0; CI: 1.02-203.3; p < 0.05) and GSTT1"-" genotype--with heavy course of disease (OR = 4.64; CI: 1.16-19.34; p < 0.05). Passive smoking was the risk factor for the unfavourable course of BA for the patients carrying GSTM1"-" genotype. Combination of plus genotypes protected PS patients from all unfavorable peculiarities of disease.

[Role of xenobiotic biotransformation enzymes in susceptibility to bronchial asthma and in formation of its clinical phenotypic features]. / Rol' fermentov biotransfomatsii ksenobiotikov v predraspolozhennosti k bronkhial'noi astme i formirovanii osobennostei ee klinicheskogo fenotipa.

The paper shows the impact of some mutations of CYP1A, GSTM1, GSTT1, and NAT2 genes and different combinations of alleles of these genes on susceptibility to bronchial asthma and its clinical features. Passive smoking modulates these relationships.

[Genes and enzymes of the xenobiotic-metabolizing system in cancer pathology]. / Geny i fermenty sistemy metabolizma ksenobiotikov v onkopatologii.

The paper presents the results of study on polymorfisms of xenobiotic biotransformation enzymes (CYP1A1, glutathione S-transferase MI and N-acetyltransferase 2) and p53 tumor suppressor protein in patients with lung, stomach and intestine cancer. The frequency of CYP1A1-Val allele in all studied cancer groups was 3 to 5 times higher than in healthy control group. The carriers of homozygous glutathione S-transferase M1 gene deletion and slow acetylator phenotype were also of higher lung cancer risk. The substantial increase in slow acetylator phenotype frequency was shown also in the group of intestine cancer patients. The p53 Arg/Pro polymorphism study revealed the elevated frequency of Arg allele in lung and stomach cancer groups. The risk of lung cancer for the carriers of susceptible alleles depended on the age and smoking status of the patients. The results testify to a high possibility of studied polymorphic genes to be the markers of susceptibility to oncopathologies.

[Comparison of peptide maps and functional properties of monooxygenases induced by 3-methylcholanthrene and beta-naphthoflavone]. / Sravnenie peptidnykh kart i funktsional'nykh svoistv monooksigenaz, indutsirovannykh 3-metilkholantrenom i beta-naftoflavonom.

A comparative study revealed a similarity of catalytic, spectral, electrophoretic and immunochemical properties of microsomal cytochromes P-448 (Mr = 56,000) synthesized de novo in 3-methylcholanthrene- and beta-naphthoflavone-treated rats. The identity of peptide maps of microsomal and isolated cytochromes P-448 confirms the validity of the limited proteolysis method for identification of the homogeneity of microsomal hemoproteins and for a comparison of their structures. The data obtained provide a way for evaluation of similarity and differences in the structure and enzymatic activity of various monooxygenase forms without their preliminary isolation from the microsomal membrane.

[Biosynthesis in the rat liver of a common form of monooxygenase induced by xenobiotics of a methylcholanthrene series]. / Biosintez v pecheni krys obshchei formy monooksigenazy, indutsiruemoi ksenobiotikami metilkholantrenovogo riada.

Injection of Wistar rats with five structurally different inducers of methylcholanthrene-type (polycyclic aromatic and heterocyclic hydrocarbons, chloro-derivatives of biphenyl and dibenzo-p-dioxin) results in the de novo synthesis of two P-448 hemoproteins (molecular weight 56 000 and 53 000 Da) differing in their functional and immunochemical properties in liver microsomes. A comparison of catalytic and immunochemical characteristics of five cytochrome P-448 forms (Mr = 56 000 Da) as well as the data from electrophoretic, proteolytic and inhibitory analyses revealed no differences in the preparations used, with the exception of 2,3,7,8-tetrachloro-dibenzo-p-dioxin-induced microsomes characterized by a low level of this cytochrome P-448 form and a higher molecular activity as compared with 3,4-benzpyrene and 7-ethoxyresorufin-induced microsomes. The experimental results do not confirm the hypothesis on the feasibility of induced synthesis of a variety of individual forms of monooxygenase that would correlate with the number of structural variants of inducers.

Reappraisal of the liver benzpyrene hydroxylase synthesized de novo after treatment of rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene.

The dynamics of the inductive effects of MC and TCDD upon rat liver microsomal benzpyrene hydroxylase and the main properties of the de novo synthesized hemoproteins have been compared. The inadequacy of expression of the enzyme activity per total cytochrome P-448 content has been established. It was concluded that TCDD microsomes have a relatively low content of benzpyrene hydroxylase with a higher molecular activity than the enzyme from MC microsomes.

[Detection of synthesized microsomal hemoproteins (cytochrome P-448) using autofluorography]. / Vyiavlenie sinteziruemykh mikrosomnykh gemoproteidov (tsitokhromov P-448) s pomoshch'iu avtofliuorografii.

Simple and informative method for the elucidation of de novo synthesized forms of microsomal cytochrome P-448 induced by 3-methylcholanthrene and 2,3,7,8-tetrachlordibenzo-p-dioxine has been developed. The method is based on gel fluorography upon electrophoretic separation of microsomal proteins obtained from the liver of rats pre-treated with the inducers of monooxygenase system components and then with 14C-leucine. At least two forms of cytochrome P-448 (with molecular weight of 56000 and 53000) were shown to be de novo synthesized under the influence of 3-methylcholanthrene and 2,3,7,8-tetrachlodbibenzo-p-dioxine.