The risk of anti-tuberculosis (ATB) drug-induced liver injury could be determined by genotype polymorphism of the xenobiotic-metabolizing enzymes. The aim of presented research was the investigation of an impact of CYP3A4*1G polymorphism on liver function in patients with TB during anti-tuberculosis therapy. There were analyzed case histories of 105 patients with newly diagnosed pulmonary TB at Odessa Regional TB Hospital in 2012-2014. We have considered their medical records at the beginning and at the end of inpatient treatment including activity of biochemical indices such as total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutathione transferase (GGT). The genotype CYP3A4*1G, 20230G>A was detected by PCR. At the beginning of the treatment the level of studied biochemical indices was almost the same regardless of CYP3A4*1G genotype. After the conducted in-patient treatment the biochemical indices in fast metabolizers insignificantly increased, while the level of bilirubin dropped by 10.4% (p<0.05). In slow metabolizers after in-patient treatment the serum total bilirubin level increased by 8.0% (p<0.05), the activity of ALT raised by 67.2% (p<0.05), AST – by 37.4% (p>0.05), also the number of the patients with ALT and AST level beyond normal almost doubled. After completion of in-patient treatment in moderate and slow metabolizers serum GGT activity increased by 2.5 times (p<0.05) and 1.3 times (p>0.05) correspondently, among fast metabolizers – on the contrary, the number of the individuals with increased GGT level dropped (p<0.05). Thus in slow metabolizers according to CYP3A4*1G genotype after completion of in-patient stage of anti-TB treatment the level of cytolysis and toxicity indexes was much higher than in fast metabolizers. That is why detection of CYP3A4*1G genotype of TB patients at the beginning of TB treatment could help to recognize a group of the individuals with increased risk of liver injury during therapy.
Bakground: The level of antituberculosis (TB) agents and risk of anti-TB drug-induced liver injury could be predicted by patients' genotype polymorphism of the xenobiotic-metabolizsing enzymes. For example, detection of N-acetyltransferase 2 genotype in TB-patients is very valuable in this relation. Aim: To find the meaning of cyptochrome P-4503A4*1B (CYP3A4*1B) polymorphism in TB-patients. Materials and methods: CYP3A4*1B genotype was detected with the help of polymerase chain reaction among 105 patients with pulmonary TB. The level of rifampicin in the blood was determined spectrophotometrically. We have considered medical records at the beginning and at the end of in-patient treatment. Statistical analysis included Kruskal-Wallis, ANOVA, and Chi-square tests. Results: According to the genotype CYP3A4*1B 91.4% and 8.6% of the patients with pulmonary TB has homozygous wild-type gene (i.e., had high enzymatic activity) -AA and heterozygous AG genotype (moderate enzyme activity), correspondently. The peak of rifampicin's concentration in blood was observed 4 hrs after its intake: 16.25+/-3.92 and 15.03 +/-0.97 mcg/ml in AA and AG genotype correspondently. Thus, there was no significant difference in rifampicin concentration among TB-patients concerning CYP3A4*1B polymorphism. At the beginning of the treatment in TBpatients with AA genotype, the activity of alanine aminotransferase (ALT) and gamma-glutathione transferase (GGT) were on 53.8% and 31.8% higher than in the carriers of AG genotype, however that difference was statistically insignificant regarding to low number of AG genotypes carriers. During treatment in TB hospital in the carriers of AA genotype, the activity of ALT, AST (aspartate aminotransferase), and GGT has enhanced insignificantly, while the activity of ALT, AST, and GGT in AG genotype carriers slightly declined (P>0.05). Moreover, in the end of inpatient treatment, the rate of ALT and GGT in the carriers of AA genotype was on 123.3% (P=0.003; confidential interval = 6.77....29.73) and on 54.8% (P=0.039; confidential interval = 0.73....26.87) correspondently. Conslusion: Polymophism of CYP3A4*1B genotype is an important criterion for the development of hepatotoxicity before and during TB-treatment while it has no influence on rifampicin level in blood.
Among the factors that can influence the course and effectiveness of the treatment of pulmonary tuberculosis (TB) the genetic characteristics of patients play an important role. It is established that cytochrome (CYP) 3A4/5 is involved in metabolism of more than 30 % of xenobiotics. Consequently, the activity of this enzyme is greatly influenced by responsible genes, such as CYP3А4. The aim of the study was the investigation of prognostic value of CYP3A4 polymorphism on the course and effectiveness of anti-tuberculosis therapy in patients with pulmonary TB. Materials and methods. Using PCR method, a detection of polymorphism of CYP3A4*1B, CYP3A4*1G genes, which determine the activity of CYP3A4 enzyme, was performed in 105 patients with newly diagnosed pulmonary TB. We have revied medical records at the beginning and at the end of inpatient treatment and considered the form, extent, regression rate of TB-lesions, and the rate of smear-positive cases. A statistical analysis of study data, expressed in absolute or relative values, was done using Pearson’s chi-squared test. Results: It was established that out of 105 enrolled TB-patients 84 individuals (80,0%) carried the genotype of “rapid metabolizers” (RA), the rest – 15 (14,3%) and 6 (5,7%) individuals were “intermediate metabolizers” (IM) and “slow metabolizers” (SM) correspondently. According to CYP3A4 genotype in patients with SM and IM the bi-lateral lesions as well as the processes of pulmonary destruction and dissemination, as well as smearpositiveness occurred more frequently than in RM. For example, in IM group the dissemination was observed almost two times more frequently than in RM (Р<0,05; χ2=4,44). At the end of the in-patient treatment in SM remaining TB-infiltrates observed more often, while the resolution of consolidation registered more rarely (66,7%) than in IM and RM (81,0% and 80,0%, correspondently). Also, in SM the TB infiltrates remained more often than in RM (33,3% versus 8,3%, Р<0,05; χ2=4,44). At the same time in IM the smear-positive status remained more often than in other groups. Conclusion. Genotypes of “intermediate metabolizers” and “slow metabolizers” according to CYP3A4 genes were associated with unfavorable pulmonary disease both at initiation and at the end of in-patient phase of the TB treatment. Identification of CYP3A4 genotype in pulmonary TB patients allows allocation of the groups of high risk of unfavorable TB course. Key words: pulmonary tuberculo
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