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

CYP450-dependent interactions and toxicological consequences of hypoglycemic and antihypertensivedrugs used in treatment of children with metabolic syndrome (MS) remained unclear. Our aim was to carryout a complex estimation of metabolic syndrome and losartan mediated changes in CYP3A, CYP2C, CYP2E1mRNA expression, corresponding marker enzymes activities, liver antioxidant system and lipid peroxidationparameters of adult and pubertal rats. Wistar albino male rats of two age categories (young animals of 21days 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 – youngrats with MS+losartan; 6 – adult rats with MS+ losartan. The metabolic syndrome model was inducedby 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, lipidperoxidation parameters were carried out. Losartan administration caused increase of CYP3A, CYP2Cand CYP2E1 mRNA expression rates in both age groups. Marker enzymes, glutathione transferase andreductase rates were normalized only in adult rats. In group of pubertal animals losartan administration ledto CYP3A and CYP2C marker enzymes activities normalization. Liver reduced glutathione contents remaineddecreased in both age groups. Thus, losartan demonstrates some age-dependent effectiveness towardsnormalization of CYP450 isoforms expression rates, p-nitrophenol hydroxylase, erythromycin-N-demethylaseand diclofenac hydroxylase activities, but not glutathione system and lipid peroxidation rates

Poremećaji reprodukcijske funkcije u mužjaka štakora uzrokovani unosom tekućine bogate fruktozom od 23 dana starosti do puberteta

There is compelling evidence that a hypercaloric, high-fructose diet can cause metabolic syndrome (MetS) and a whole range of other metabolic changes. In the context of androgen deficiency, MetS in boys merits special attention, but the effects of fructose-rich diet in youth on future male reproductive function are still poorly evidenced. The aim of this study was to address this issue and analyse the effects of high-fructose intake starting from weaning to puberty (postnatal day 23 up to 83) on the reproductive function of male rats. For this purpose juvenile male Wistar rats were divided in two groups: control and the group receiving 10 % fructose solution instead of drinking water. Reproductive function was evaluated in terms of fertility, sperm count, testes/epididymis morphology, and serum sex hormones. The fructose-treated group showed a decrease in testosterone and twofold increase in luteinising and follicle-stimulating hormone levels in the serum. This was accompanied with lower testis/epididymis weights, sperm count, and changed testis/epididymis morphology. Their fertility remained unchanged, but the fertility of females mating with these males diminished. In addition, pre-implantation and post-implantation embryonic death rate rose in these females. Our results have confirmed that high fructose consumption from early age until puberty can impair the reproductive function of male rats, and call for further animal and epidemiological investigation.Postoje snažni dokazi da hiperkalorična prehrana bogata fruktozom može uzrokovati metabolički sindrom (MetS) i cijeli niz drugih promjena u metabolizmu. U smislu androgene deficijencije, MetS u dječaka izaziva posebnu pažnju, ali nema mnogo spoznaja o učincima prehrane bogate fruktozom u ranoj mladosti na buduću reprodukcijsku funkciju u muškaraca. Stoga je cilj ovoga istraživanja bio analizirati učinke unosa tekućine bogate fruktozom u mladih mužjaka štakora od trenutka kad su prestali sisati (23 dana starosti) do puberteta (83 dana starosti) na njihovu reprodukcijsku funkciju. U tu su svrhu muški Wistar štakori podijeljeni u dvije skupine: kontrolnu i onu koja je primala 10 %-tnu otopinu fruktoze umjesto vode za piće. Parametri procjene reprodukcijske funkcije obuhvatili su plodnost, broj spermija, morfologiju testisa (sjemenika) i epididimisa (pasjemenika) te razine spolnih hormona u serumu. U skupini koja je primala fruktozu zamijećeno je smanjenje razine testosterona i dvostruko povećanje razina luteinizirajućega i folikulostimulirajućega hormona u serumu u odnosu na kontrolnu skupinu. Te su promjene popraćene padom težine testisa i epididimisa, broja spermija te promjenama u morfologiji testisa i epididimisa. Plodnost im se nije promijenila, ali je zato plodnost ženki koje su se parile s mužjacima izloženima fruktozi bila smanjena. Osim toga, u tih se ženki povećala smrtnost embrija prije i nakon implantacije u odnosu na ženke koje su se parile s kontrolnim mužjacima. Naši rezultati potvrđuju pretpostavku da konzumacija hrane i pića bogatih fruktozom od rane dobi do puberteta može oštetiti reprodukcijsku funkciju u štakora. Stoga je potrebno provesti daljnja istraživanja u životinja te epidemiološka istraživanja u ljudi

Effects of Metformin and Preparations With Pleiotropic Effects on Testicular Biochemical Indices of Rats With Juvenile-Onset Metabolic Syndrome

Background. Metabolic syndrome (MS) is a complex of disorders characterized by abdominal obesity, insulin resistance and glucose tolerance, arterial hypertension, and all types of metabolic disorders. Taking into account the wide range of symptoms accompanying MS, the use of preparations with pleiotropic effects on metabolic processes in the body could be promising for its treatment. Objective. The aim of this study is comparative estimation of metformin or its combination with vitamins' complex or liposomal preparation treatment effects on DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes in testes of rats with MS induced in juvenile age. Methods. MS model was induced by full replacement of drinking water with 10% fructose solution in Wistar male rats of 21–23 days age (50–70 g). DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes investigations were carried out after 60 days of MS modeling and metformin or its combination with vitamins' complex or liposomal preparation treatment. Results. In experiments with pubertal rats with MS and metformin or its combination vitamins' complex or liposomal preparation treatment, we established partially corrective effects of these medications for DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes changes caused by MS development. Conclusions. A comparative analysis of the studied preparations' effects under MS simulation in the juvenile age showed that none of these drugs was able to completely normalize the disorders in studied indicators caused by MS. However, both combinations of metformin with vitamins' complex or liposomal preparation were still more effective in these negative changes' correction then metformin itself. Metformin with vitamins' complex caused a more pronounced influence on the processes of DNA fragmentation, the levels of adenyl nucleotides, and the energy charge of rat testicular cells, while the corrective effect of metformin with liposomal preparation was more noticeable with respect to the content of chromatin components

Ekspresija CYP2E1 u testisima štakora i alkoholom prouzrokovane promjene indeksa spermatogeneze i kolagena tipa I

This study is a complex investigation of alcohol-mediated changes in CYP2E1 mRNA and protein expression in the testes, as well as spermatogenesis indices and type I collagen amino acid contents, in male rats. Wistar albino male rats were divided into two groups: I – control (intact animals), II – experimental (chronic alcoholism, exposure to a 15 % ethanol aqueous solution during 150 days). The destructive changes in the spermatogenic epithelium were accompanied by a decrease in sperm number and motility time. CYP2E1 mRNA and protein expression were elevated in the testes 3 and 1.4 times, respectively. Also, significantly lower contents of lysine, glutamic acid, serine, proline, alanine, valine, and phenylalanine residues accompanied by an increase of hydroxyproline, glycine, and threonine residue contents were detected in the skin type I collagen of the experimental group. Chronic ethanol consumption caused testicular failure along with an overexpression of CYP2E1 mRNA and protein in the testes as well as quantitative changes in type I collagen amino acid contents. The profound alcohol-mediated changes in collagen type I amino acid contents may have affected the spermatogenic epithelium state. The modulation of testicular cytochrome P450 2E1 mRNA and protein expression could change the functioning of this isozyme in target organs and take part in the mechanism of ethanol gonadotoxicity.Ovo istraživanje proučava alkoholom uzrokovane promjene u ekspresiji CYP2E1 mRNA i bjelančevina iz testisa, indeksu spermatogeneze i aminokiselinskom sastavu kolagena tipa I u muških štakora. Albino štakori tipa Wistar podijeljeni su u dvije skupine: I – kontrolna, II – eksperimentalna (kronični alkoholizam, izloženi 150 dana 15-postotnoj vodenoj otopini etanola). Destruktivne promjene u spermatogenetskom epitelu popraćene su smanjenjem broja i pokretljivosti spermija. Ekspresija mRNA gena CYP2E1 i bjelančevina bila je povišena u testisima 3, odnosno 1,4 puta. Također, u kolagenu tipa I ustanovljene su značajno manje količine lizina, glutaminske kiseline, serina, prolina, alanina, valina i fenilalanina, te veće količine ostataka hidroksiprolina, glicina i treonina. Kronična konzumacija etanola uzrokovala je otkazivanje testisa uz izraženu ekspresiju mRNA CYP2E1 i bjelančevina u testisima, te kvantitativne promjene u aminokiselinama kolagena tipa I. Izražene alkoholom prouzrokovane promjene mogle su utjecati na spermatogenetski epitel. Modulacija ekspresije mRNA testikularnog citokroma P450-2E1 i bjelančevina mogla bi promijeniti djelovanje ovoga izozima u ciljnim organima te sudjelovati u mehanizmu gonadotoksičnosti etanola

Metabolic syndrome and losartan treatment effects in adult and pubertal rats

Introduction: Comparative estimation of losartan treatment effects in adult and pubertal rats with metabolic syndrome (MS). Material and methods: MS model was induced by full replacement of drinking water with 20% fructose solution at Wistar male rats of two age categories: young animals of 21–23 days age (50–70 g) and adults (160–180 g). Clinical hematology and biochemistry tests, blood pressure measurement, chromatin DNA fragmentation, and liver morphological investigations were carried out after 60 days of MS modeling and losartan treatment. Results: Effects of losartan on blood clotting time, lipid metabolism, and DNA fragmentation were more pronounced in pubertal rats, while more profound influence on high-density lipoprotein (HDL) contents, pancreas, and visceral fat relative weights was found in adults. Conclusions: In pubertal and adult rats with MS, losartan effects were age-dependent for lipid metabolism indices, blood clotting time, nuclear DNA fragmentation, relative organs weights, and liver morphologic structure. Losartan treatment normalized blood pressure independently of age, while its effects on other parameters in adults and young rats differed not only in their degree of manifestation but also in their very nature