ABSTRACT
ABSTRACT Introduction: Homocysteine (Hcy) is one of the metabolites of methionine (Met), an essential diet-derived amino acid. There is a close relationship between high plasma Hcy levels and declining renal function. Plasma and urinary Hcy level has been the target of studies as a biomarker that forecasts poor outcome in renal patients and in hemodialysis patients. This review evaluates the main studies that sought to correlate Hcy and poor prognosis in renal disease as well as the treatments proposed for the reduction of plasma Hcy levels in these patients. Conclusion: Hcy could be an important biomarker of renal disease progression mainly in hemodialysis patients. We emphasize the importance of normalizing plasma levels of this amino acid to ensure a better prognosis in kidney disease.
RESUMO Introdução: A homocisteína (Hcy) é um dos metabólitos da metionina (Met), um aminoácido essencial proveniente da dieta. Existe uma estreita relação entre os altos níveis plasmáticos de Hcy e o declínio da função renal. A Hcy plasmática e urinária tem sido alvo de estudos como um biomarcador capaz de sinalizar o prognóstico em doentes renais e em pacientes em hemodiálise. Esta revisão avalia os principais estudos que buscaram correlacionar a Hcy e o prognóstico da doença renal e descreve os tratamentos propostos para a redução dos níveis plasmáticos de Hcy nesses pacientes. Conclusão: A Hcy pode ser um biomarcador da progressão na doença renal, principalmente em pacientes hemodialíticos. Ressaltamos a importância da normalização dos níveis plasmáticos desse aminoácido para garantir um melhor prognóstico na doença renal.
ABSTRACT
Liver microsomal cytochrome P4502E1-dependent p-nitrophenol (PNP) hydroxylation and expression of cytochrome P4502E1 were studied in rats subjected to gamma-hexachlorocyclohexane (HCCH) or L-3,3,5-triiodothyronine (T3) administration as a possible mechanism contributing to superoxide radical (O2.-) generation. HCCH treatment (a single dose of 40 mg/kg body wt) produced a 43 per cent increase in the content of total cytochrome P450, whereas T3 (daily doses of 0.1 mg/kg body wt for two consecutive days) led to a 37 per cent decrease. NADPH-dependent O2.- generation was elevated by HCCH and T3, expressed as either per mg of protein or per nmol of cytochrome P450, with a 135 per cent enhancement in the O2.- production/superoxide dismutase (SOD) activity ratios being observed in both conditions. This was partly due to depression of SOD activity. Concomitantly, the molecular activity of NADPH-cytochrome p450 reductase was enhanced by 90 and 69 per cent by HCCH and T3, respectively. In these conditions, microsomal PNP hydroxylation showed increases of 58 and 45 per cent in HCCH- and T3-treated rats over control values, respectively, with a parallel 31 per cent (HCCH) and 41 per cent (T3) enhancement in the content of cytochrome P4502E1 assessed by western immunoblotting. We conclude that HCCH and T3 enhance the expression and activity of cytochrome P4502E1 and that of NADPH-cytochrome P450 reductase in rat liver, regardless of the changes in total cytochrome P450 content, representing major contributory mechanisms to microsomal NADPH-dependent O2.- generation.
Subject(s)
Animals , Male , Rats , Liver , Microsomes, Liver , Liver , Rats, Sprague-Dawley , Reactive Oxygen SpeciesABSTRACT
Cytotoxicity induced by xenobiotics and hormonal changes is a complex event, comprising primary and secondary mechanisms whose joint operation may lead to irreversible molecular changes associated with cell death. In this respect, alcoholic liver cell necrosis may be conditioned either by the generation of ethanol-derived acetaldehyde leading to covalent binding to biomolecules and derangement of key metabolic functions, the production of hypoxic damage secondary to elevated O2 uptake, impairment of membrane functions upon reduction in membrane fluidity, and/or by the development of oxidative stress. The latter mechanism is involved in the hepatotoxic effects of lindane, involving both early direct actions related to the biotransformation of the insecticide and late adaptive changes derived from cytochrome P-450 induction. Thyroid calorigenesis involving an accelerated rate of O2 consumption in the liver determines an increased oxidative stress status due to higher rates of O2 and/or H2O2 production by microsomal, mitochondrial, and peroxisomal electron transport systems, with diminished antioxidant defenses. Hyperthyroidism-induced liver oxidative stress may be associated with cell injury, altered hepatic functions, and potentiation of toxicity by xenobiotics. Liver oxidative stress may be secondarily exacerbated by neutrophil infiltration and/or alterations in Kupffer cell function. These phagocytes release chemical mediators and respiratory burst-related reactive O2 species upon stimulation in the liver, which are potentially toxic for parenchymal cells. As the different factors underlying oxidative stress and the interrelationships between oxidative stress and other cytotoxic mechanisms become better defined preventive and protective interventions will become more clear.