Liver microsomal parameters related to oxidative stress and antioxidant systems in hyperthyroid rats subjected to acute lindane treatment

Liver microsomal functions related to xenobiotic biotransformation and free radical production were studied in control rats and in animals subjected to L-3,3',5-triiodothyronine (T-3) and/or lindane administration as possible mechanisms contributing to oxidative stress, in relation to the activity of enzymes (superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glucose-6-phosphate dehydrogenase (G-6PDH) and content of lipid-soluble vitamins (alpha-tocopherol, beta-carotene, and lycopene) affording antioxidant protection. Lindane treatment in euthyroid rats at a dosage of 20 mg/kg did not modify the content of liver microsomal cytochromes P450 and b(5), the activity of NADPH-cytochrome P450 reductase and NADH-cytochrome b(5) reductase, and the production of superoxide radical (O-2(.-)), as well as antioxidant systems, except for the reduction in lycopene levels. Hyperthyroidism elicited a calorigenic response and increased specific and molecular activities of NADPH-cytochrome P450 reductase, O-2(.-) generation, and G-6PDH activity, concomitantly with diminution in liver SOD and catalase activities and in alpha-tocopherol, beta-carotene, and lycopene levels. the administration of Lindane to hyperthyroid animals led to a further increase in the molecular activity of NADPH-cytochrome P450 reductase and in the O-2(.-) production/SOD activity ratio, and decrease of hepatic alpha-tocopherol content, in a magnitude exceeding the sum of effects elicited by the separate treatments, as previously reported for reduced glutathione depletion. Collectively, these data support the contention that the increased susceptibility of the liver to the toxic effects of acute lindane treatment in hyperthyroid state is conditioned by potentiation of the hepatic oxidative stress status.Univ Chile, Fac Med, Inst Ciencias Biomed, Programa Farmacol Mol & Clin, Santiago 7, ChileUniv São Paulo, Inst Quim, Dept Bioquim, BR-01498 São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Estudos Envelhecimento, São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Estudos Envelhecimento, São Paulo, BrazilWeb of Scienc

alpha-Tocopherol modulates tyrosine phosphorylation in human neutrophils by inhibition of protein kinase C activity and activation of tyrosine phosphatases

alpha-Tocopherol augmentation in human neutrophils was investigated for effects on neutrophil activation and tyrosine phosphorylation of proteins, through its modulation of protein kinase C (PKC) and tyrosine phosphatase activities. Incubation of neutrophils with alpha-tocopherol succinate (TS) resulted in a dose-dependent incorporation into cell membranes, up to 2.5 nmol/2 X 10(6) cells. A saturating dose of TS (40 mumol/l) inhibited oxidant production by neutrophils stimulated with phorbol myristate acetate (PMA) or opsonized zymosan (OZ) by 86 and 57%, as measured by luminol-amplified chemiluminescence (CL). With PMA, TS inhibited CL generation to a similar extent to staurosporine (10 nmol/l) or genistein (100 mumol/l), and much more than Trolox (40 mumol/l). With OZ, TS inhibited CL to a similar extent to Trolox. Neutrophil PKC activity was inhibited 50% or more by TS or staurosporine. the enzyme activity was unaffected by genistein or Trolox, indicating a specific interaction of alpha-tocopherol. TS or Trolox increased protein tyrosine phosphorylation in resting neutrophils, and as with staurosporine further increased tyrosine phosphorylation in PMA-stimulated neutrophils, while the tyrosine kinase (TK) inhibitor genistein diminished phosphorylation. These effects in resting or PMA-stimulated neutrophils were unrelated to protein tyrosine phosphatase (PTP) activities, which were maintained or increased by TS or Trolox. in OZ-stimulated neutrophils, on the other hand, all four compounds inhibited the increase in tyrosine-phosphorylated proteins. in this case, the effects of pre-incubation with TS or Trolox corresponded with partial inhibition of the marked (85%) decrease in PTP activity induced by OZ. These results indicate that alpha-tocopherol inhibits PMA-activation of human neutrophils by inhibition of PKC activity, and inhibits tyrosine phosphorylation and activation of OZ-stimulated neutrophils also through inhibition of phosphatase inactivation.UNIFESP, Disciplina Geriatr, Dept Med, EPM, BR-04038032 São Paulo, BrazilUniv São Paulo, Inst Quim, São Paulo, BrazilFdn Pro Sangue, Hemoctr São Paulo, São Paulo, BrazilNYU, Med Ctr, New York, NY 10016 USAUNIFESP, Disciplina Geriatr, Dept Med, EPM, BR-04038032 São Paulo, BrazilWeb of Scienc

Antioxidant defense in rat brain after chronic treatment with anorectic drugs

Mazindol (5-hydroxy-5-p-chlorophenyl-2,3-dihydro-5H-isoindole) although not chemically related to the phenylethylamine group, shows a pharmacological profile similar to that of amphetamines. in rats these anorectic drugs enhance dopamine (DA) turnover, which is the mechanism that causes anorexia. It has been hypothesized that amphetamine causes a long-lasting depletion of DA, a decrease of dopaminergic transport pumps and nerve terminal degeneration increasing. These actions provide a cellular environment encouraging the autoxidation of DA that may lead to lipid peroxidation and neuronal damage. Considering that both drugs may cause neuronal damage by oxidative mechanisms, this study was conducted to investigate the action of mazindol and methamphetamine on brain cell antioxidant defense system and to investigate whether animal age is important in the antioxidant response to chronic anorectic administration. the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the total glutathione (GSH) content in brains of rats, were measured. the animals (2 groups with 5 and 18 months old) were treated for 5 months (i.p.) with mazindol (10 mg/kg body weight/day), methamphetamine (2.5 mg/kg body weight/day) or saline. the results obtained showed no differences between SOD, CAT, GPx activities and GSH content in the brain of animals treated with saline compared with both drugs, either in 10-month or 23-month groups. On the other hand, brain total GSH content of old animals was found to be lower than that from young ones, independent of the treatment. SOD activity was found to be increased, CAT unchanged and GPx decreased, in the brain of old animals, treated with both drugs or saline. These findings led us to conclude that the chronic administration of mazindol and methamphetamine have no effects on the antioxidant systems studied either in young (10 months) or in old (23 months) rats.Universidade Federal de São Paulo,ESCOLA PAULISTA MED,DEPT PSYCHOBIOL,São Paulo,BRAZILUniversidade Federal de São Paulo,ESCOLA PAULISTA MED,DEPT PSYCHOBIOL,São Paulo,BRAZILWeb of Scienc