Losartan effects on liver cytochromes CYP3A, CYP2C and CYP2E1 functioning at metabolic syndrome in young and adult rats

Abstract

CYP450-dependent interactions and toxicological consequences of hypoglycemic and antihypertensive drugs used in treatment of children with metabolic syndrome (MS) remained unclear. Our aim was to carry out a complex estimation of metabolic syndrome and losartan mediated changes in CYP3A, CYP2C, CYP2E1 mRNA expression, corresponding marker enzymes activities, liver antioxidant system and lipid peroxidation parameters of adult and pubertal rats. Wistar albino male rats of two age categories (young animals of 21 days age (50-70 g) and adults (160-180 g) were divided into 6 groups (6 animals in each): 1 -Control 1 (intact young rats); 2 -Control 2 (intact adult rats); 3 -young rats with MS; 4 -adult rats with MS; 5 -young rats with MS+losartan; 6 -adult rats with MS+ losartan. The metabolic syndrome model was induced by full replacement of drinking water with 20% fructose solution (200 g/l). After 60 days of MS modeling, investigation of rat liver CYP3A, CYP2C, CYP2E1 mRNA expression, their marker enzymes activities, lipid peroxidation parameters were carried out. Losartan administration caused increase of CYP3A, CYP2Cand CYP2E1 mRNA expression rates in both age groups. Marker enzymes, glutathione transferase and reductase rates were normalized only in adult rats. In group of pubertal animals losartan administration led to CYP3A and CYP2C marker enzymes activities normalization. Liver reduced glutathione contents remained decreased in both age groups. Thus, losartan demonstrates some age-dependent effectiveness towards normalization of CYP450 isoforms expression rates, p-nitrophenol hydroxylase, erythromycin-N-demethylase and diclofenac hydroxylase activities, but not glutathione system and lipid peroxidation rates.

In Vitro Hepatic Assessment of Cineole and Its Derivatives in Common Brushtail Possums (Trichosurus vulpecula) and Rodents

“…Moreover, there is no direct evidence that supports the basal CYP3A catalytic activities in possums; however, Sorensen, et al [ 23 ] reported that possums express at least three different CYP3A-like isoforms (CYP3A P1, P2, P3) in their liver and duodenum that may contribute to a high tolerance for a wide range of xenobiotics. In mice, the basal level of hepatic CYP3A catalytic activities was similar (<1 nmol/min per mg protein) to those reported previously [ 24 , 25 ]. Even though there were basal differences, none of the tested compounds up to 50 µM showed any significant inhibition of CYP3A catalytic activity in mouse, rat, and possum hepatic microsomes.…”