Shayakhmetova A. The particularities of the adverse antituberculosis drugs reactions on male reproductive function and proof of the approaches to their pharmacological correction (experimental study)

The dissertation describes the experimental foundation of the particularities of the adverse antituberculosis drugs reactions on male reproductive function and proof of the approaches to their pharmacological correction. Basically, administration of the ATD combination into male rats having experimental chronic alcoholism led to a progressive increase in hepatic and testicular CYP2E1 gene expression level 5 and 5.9 folds, respectively, as well as an elevation 1.5 folds of p-nitrophenol hydroxylase (a marker of CYP2E1) activity in microsomal fraction of liver cells as compared with rats, which consumed alcohol without ATD, and tripled elevation in comparison with the control group. In general, the results of the investigations evident the worsening in abnormalities of spermatogenic epithelium cells differentiation and disturbances in normospermia in alcoholic rats, that received a combination of ATD. The histological examination of spermatogenic epithelium revealed that in group of animals with chronic alcoholism proportion of epithelium exfoliation into the lumen of tubules was increased 4 folds, while in the group with administration of ATD – 5 folds; proportion of the vacuoles occurrences rose 7 and 9 folds in each group, respectively; the number of spermatogonia decreased in 14 % and 20 % in comparison with control. Spermatogenetic disorders as well as reduction of sperm quantity and quality in male rats receiving ATD with ethanol exposure, led to a significant decrease in fertility and 100 % post-implantation death of offspring, when mated with intact females. Finally, the investigations of the drugs capable to inhibit CYP2E1 demonstrated that effects on reproductive function of male rats with ATD administration included following: 1. Methionine and a composition of biologically active substances - Metovitan inhibited transcriptional activation of CYP2E1 gene and its enzymatic activity in testes, thereby preventing changes in testicular pro/antioxidant systems. Moreover, Metovitan inhibited expression of CYP2E1 mRNA and its catalytic activity more efficiently compared with methionine. Accordingly, it contributed to the maintenance of the seminiferous epithelium integrity, the increase of sperm count and the enhance of male rats fertility. As such, these promising results are serving as the experimental proof of prospective use of substances that inhibit such enzyme isoform and have antioxidant properties in the treatments of male subfertility and infertility, especially in the case of receiving chemotherapeutic agents capable to induce CYP2E1 and conditions associated with its induction.