Can we assess the CYP3A4*1G polymorphism as a predictor of the hepatotoxicity during antituberculosis therapy?

Abstract

The aim of this research was to find the meaning of CYP3A4*1G polymorphism in TB patients for the toxicity development during inpatient TB treatment. Figure Thus according to CYP3A4*1G genotype after completion of in-patient stage of anti-TB treatment the intensity of cytolysis and hepatotoxicity indices in “slow metabolizers” were much higher than in “rapid metabolizers”. That is why, the detection of CYP3A4*1G genotype in TB patients at the beginning of TB treatment could help to recognize the individuals with high risk of liver injury who need additional medical care. This work was supported by the special scientific research program of the Healthcare Ministry of Ukraine (№0121U107508). Results CYP3A4*1G genotyping of 105 patients has shown that 91.4% had no mutation in this region (*1/*1 genotype; “rapid metabolizers”), 4.8% had one mutated allele (*1/*1G genotype; “intermediate metabolizers”), and 3.8% had both mutated alleles (*1G/*1G genotype; “slow metabolizers”). At the beginning of the treatment the level of studied biochemical indices was almost the same regardless of CYP3A4*1G genotype. After the conducted inpatient treatment in “rapid metabolizers” studied biochemical indexes insignificantly increased, while the level of bilirubin has dropped on 10,4% (p=0,023; СІ=-2,85…-0,21). In “slow metabolizers” after inpatient treatment the serum total bilirubin level increased on 8,0% (p<0,001; СІ=2,33…6,03), the activity of ALT raised on 67,2% (p=0.033; CI=- 30,14…-1,86), AST - on 37,4% (p>0,05) comparatively to the initial level; also the amount of the patients with ALT and AST level beyond normal almost doubled. In result of inpatient treatment in “intermediate metabolizers” the activity of serum ALT and AST increased in 1.5 times (p>0,05). After completion of inpatient treatment in “intermediate metabolizers” and in “slow metabolizers” serum GGT activity increased in 2,5 times (p<0,05) and 1,3 times (p>0,05) correspondently; among ”rapid metabolizers” – on the contrary, the number of the individuals with increased GGT level has dropped (p<0,05). According to obtained results the presence of variant alleles (“slow metabolizers” genotype) is accompanied by slowing down of the conjugation stage rate in liver that is approved by increasing of bilirubin level. In addition, this genotype is associated with more intensive cytolysis of hepatocytes that is witnessed by raising of ALT and ACT activity in the blood. Design Method Blood samples were obtained from 105 patients with newly diagnosed pulmonary TB at Odessa Regional TB Hospital in 2015. The study was approved by Ethical Commission of Odessa National Medical University. DNA material was extracted from the blood using a kit of DNA-Sorb-B. A CYP3A4*1G genotype was detected with the help of PCR according to Yuan Gao, et al. 2008. All TB patients were receiving complex therapy recommended by the World Health Organization DOTS strategy. We have considered medical records at the beginning and at the end of inpatient treatment including activity of biochemical indices such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gammaglutathione transferase (GGT), and total bilirubin level in blood serum.