Human N-acetyltransferases and drug-induced hepatotoxicity.

There are a lot of pharmaceutical substances nowadays on the market. More than 1000 drugs have been implicated in causing liver diseases in more than one occasion. The liver is the most massive and important internal organ of human body. The morphological and functional integrity of the liver is vital to the health of the human organism. Xenobiotic biotransformation is the principal mechanism for maintaining homeostasis during exposure of organisms to small foreign molecules, such as drugs. Most drugs are lipophilic and they become more hydrophilic by xenobiotic metabolizing enzymes. Arylamine N acetyltransferases (NAT) convert aromatic amines or hydrazines to aromatic amides and hydrazides. A lot of generally used drugs contain aromatic amine or hydrazine groups. Drug-induced liver injury (DILI) is the grave problem in the present world. The frequency of DILI is 15-40 cases per 100000 persons per year with 6 % mortality rate on average. This review is devoted to the analyses of arylamine N-acetyltransferases role in DILI. The NAT gene polymorphism and slow phenotype are associated with predisposition to hepatotoxicity during drug-specific treatment. NAT activity is changed by smoking, viral infections and variety of drugs. It is shown that the involving of NAT in pathogenic processes of DILI such as inflammatory or immune response, formation reactive metabolites, oxidative stress, cholestasis.

Antioxidant and endothelium-stabilizing effects of simvaglyzin on rabbits with experimental hypercholesterolemia.

Simvaglyzin, a complex compound of simvastatin and glycyrrhizic acid, administered to rabbits with experimental hypercholesterolemiain in doses equivalent to 66.6 and 40 microg/kg simvastatin exhibited antioxidant capacity (decreased the content of lipid peroxidation products in the blood by 27-41%) and endothelium-normalizing effect (decreased the level of von Willebrand factor and endothelin-1 by 26-58 and 21-29%, respectively, compared to 200 microg/kg simvastatin, p<0.05).

Analysis of associations of NAT2 gene polymorphisms with the risk of lung cancer.

The incidence of 5 polymorphisms of N-acetyltransferase-2 gene was evaluated in patients with lung cancer. A803G polymorphism is a factor of lung cancer resistance in tobacco smoking Caucasians in Novosibirsk. Opposite effects of NAT2 gene polymorphisms on the risk of lung cancer are possible.

Polymorphism of arylamine-N-acetyltransferase 2 gene is associated with the risk of atopic dermatitis.

A case--control study was conducted to evaluate the relationship between C481T and G590A polymorphisms of arylamine-N-acetyltransferase 2 and predisposition to atopic dermatitis in children. Double heterozygote 481C/T and 590G/A in girls is a factor of resistance to atopic dermatitis, especially in the absence of smoking-related effects.

[Restriction analysis of N-acetyltransferase 2 gene in Caucasian population of West Siberia]. / Restriktsionnyi analiz gena N-atsetiltransferazy (NAT2) u evropeoidov zapadnoi Sibiri.

Restriction analysis of the NAT2 gene was carried out in inhabitants of Novosibirsk. Polymorphism of this gene for nine known point mutations was studied in a sample of Novosibirsk residents consisting of 109 healthy Caucasians. The frequencies of these mutations did not significantly differ from the frequencies reported for Caucasian populations of other countries. In 79 patients with lung cancer, a region of the NAT2 gene that includes 29.7% of the coding sequence was analyzed for the new mutations by the RFLP analysis. No new mutations were found in this group.

[Polymorphic genes of xenobiotic-metabolizing enzymes associated with bronchial asthma in genetically predisposed children]. / Assotsiatsiia polimorfnykh genov fermentov biotransformatsii ksenobiotikov s predraspolozhennost'iu k bronkhial'noi astme u detei s nasledstvennoi otiagoshchennost'iu i bez takovoi.

The frequencies of the CYP1A1 valine allele, homozygous deletions of GSTM1 and GSTT1, and two point mutations of the NAT2 gene, (C481-->T) and S2 (G590-->A), were compared in healthy children and children having bronchial asthma. The S1 mutation was associated with resistance, and all of the other traits, with predisposition to the disease. In families of patients with diseased progenitors and in those with healthy progenitors, the estimates of the asthma risk were similar. In both groups, parameters of the trait association with the disease depended on passive smoking. At passive smoking, a trend to an overrepresentation (high odds ratio, OR) of the GSTM1 null genotype and S2 mutation of the NAT2 gene was observed, whereas the odds ratio of the GSTT1 null genotype decreased, and those of the CYP1A1 and S1 mutation of the NAT2 gene remained unchanged. The highest OR = 36.25 (P < 0.01) was characteristic of the GSTT1 null genotype in nonsmoking hereditary burdened patients. The results obtained suggest an important role of xenobiotic-metabolizing enzymes in development of bronchial asthma.

Allele NAT2*5 determines resistance to bronchial asthma in children.

NAT2*5 allele was found in 54.8% healthy children and 35.9% children with bronchial asthma, i.e. the risk of bronchial asthma was considerably lower in individuals carrying NAT2*5 allele. NAT2*5 allele manifests itself in both homo- and heterozygous states.

[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.