EFFECT OF HYPERHOMOCYSTEINEMIA ON THE METABOLISM OF SULFUR-CONTAINING AMINO ACIDS IN THE KIDNEYS OF RATS WITH HYPER- AND HYPOTHYROIDISM

Abstract

Hyperhomocysteinemia (HHC) is an independent risk factor for premature atherosclerotic vascular disease and venous thrombosis. It is known that hypothyroidism is associated with a mild case of HHC, an increased risk of cardiovascular, coronary heart diseases. High concentration of homocysteine (Hcy) in the blood plasma is an independent risk factor for atherosclerosis. It was established that patients with hypothyroidism have moderately elevated levels of Hcy that are normalized after hormone replacement therapy.

The aim of the study – to establish the effect of experimental hyper- and hypothyroidism at HHcy on the processes of remethylation cycle and transsulfuration pathway of sulfur-containing amino acids exchange in the kidneys, the concentration of Hcy, cysteine, and hydrogen sulfide (H₂S) in the serum blood of rats.

Materials and Methods. The research was performed on white male rats, which were simulated HHC, hyper- and hypothyroidism, HHC with different functions of the thyroid gland. The activity of S-adenosylmethionine synthetase (S-AMS), S-adenosylhomocysteine hydrolase (S-AHH), betaine-homocysteine methyltransferase (BHMT), cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and cysteine aminotransferase (CAT), γ-glutamylcysteine ligase (γ-GCL), cysteine dioxygenase (CDO), sulfite oxidase (SO), thiosulfate-dithiol sulfurtransferase (TST) was determined in kidneys. Total concentration of HCy, cysteine, H₂S was determined in the blood serum.

Results and Discussion. Experimental HHC causes disorders of functioning in kidneys of the enzymes of the Hcy remethylation cycle due to a decrease in S-AMS and BHMT activity and cysteine ​​catabolism – CDO, increases the concentration of Hcy and cysteine ​​and decreases concetration of H₂S in the blood serum compared to the control group. The hyperthyroidism performed by the administration of L-thyroxin to rats leads to an increase in kidney activity of enzymes responsible for metabolism of Hcy (S-AMC, S-AHH, BHMT) and cysteine ​​(CDO, GCL, CBS, CGL, CAT) compared to the control group of animals. Such changes in the activity of enzymes lead to a decrease in the level of Hcy in the blood as compared with the control, as well as an increase in the production of H₂S as compared with the group of animals with HHcy. Hypothyroidism in rats causes inhibition of the process of remethylation and transsulfuration cycles. In this case, the level of Hcy and cysteine ​​increases significantly in the serum compared with the control. The activity of the enzyme remethylation cycle was decreased (S-AMS, S-AHH, BHMT). The activity of GCL, which is responsible for the utilization of cysteine, significantly increased, while the activity of CDO, TST, and CO significantly decreased compared with the control group. The administration of L-thyroxine in animals with HHcy led to a slight increase in the activity of enzymes of the remethylation cycle (S-AHH, BHMT), catabolism and cysteine ​​(GCL) compared with the group of animals with HHcy. At the same time, the administration of mercazole to animals with HHC led to opposite changes in the activity of enzymes of remethylation cycle (S-AMS, S-AHH) and transsulfuration (CBS and CSE), the activity of enzymes were decreased compared to the control group of animals.

Conclusions. The described metabolic mechanisms are obviously one of the causes of the violation of cardiovascular diseases and increased thrombosis that occur in patients with hypothyroidism and may be due to violations of sulfur-containing amino acid metabolism disoders, leading to the HHC and decrease of H₂S levels.