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Metabolic Inhibition (metabolic + inhibition)
Selected AbstractsHepatic microsomal cytochrome P450 enzyme activity in relation to in vitro metabolism/inhibition of polychlorinated biphenyls and testosterone in Baltic grey seal (Halichoerus grypus)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2003Hongxia Li Abstract Among other factors, cytochrome P450 (CYP) enzyme activity determines polychlorinated biphenyl (PCB) bioaccu-mulation, biotransformation, and toxicity in exposed species. We measured the oxidative metabolism in vitro of 12 PCB congeners, representing structural groups based on the number and position of the chlorine atoms, by the hepatic microsomes of one Baltic grey seal (Halichoerus grypus). Microsomal metabolism was observed for several PCBs with vicinal H atoms exclusively in the ortho and meta positions and without any ortho -Cl substituents (CB-15 [4,4,-Cl2] and CB-77 [3,3,,4,4,-Cl4]), vicinal meta and para -H atoms (CB-52 [2,2,,5,5,-Cl4], and ,101 [2,2,,4,5,5,-Cl5]) or with both characteristics in combination with either only one ortho -Cl (CB-26 [2,3,,5-Cl3], CB-31 [2,4,,5-Cl3]) or two ortho -Cl substituents (CB-44 [2,2,,3,5,-Cl4]). To allocate PCB biotransformation to specific CYPs, the inhibitive effect of compounds with known CYP-specific inhibition properties was assessed on in vitro PCB metabolism and on regio- and stereospecific testosterone hydroxylase activities. Metabolic inhibition was considered relevant at concentrations ,1.0 ,M because these inhibitors became decreasingly selective at higher concentrations. At <1.0 ,M, ellipticine (CYP1A1/2 inhibitor) selectively inhibited CB-15, ,26, ,31, and ,77 metabolism, with no significant inhibition of CB-44, ,52, and ,101 metabolism. Inhibition of CB-52 and ,101 metabolism by chloramphenicol (CYP2B inhibitor) started at 1.0 ,M and maximized at about 100% at 10 ,M. Ketoconazole (CYP3A inhibitor) appeared to selectively inhibit CB-26, ,31, and ,44 metabolism relative to CB-15, ,77, and ,52 at concentrations ,1.0 ,M. Major testosterone metabolites formed in vitro were 2,-(CYP3A), 6,- (CYP3A, CYP1A), and 16,- (CYP2B) hydroxytestosterone and androstenedione (CYP2B, CYP2C11). The CYP forms indicated are associated with the specific metabolism of testosterone in laboratory animals. Inhibition of 2,- and 6,-hydroxytestosterone formation at ellipticine and ketoconazole concentrations ,1.0,M suggested that both inhibitors were good substrates of CYP3A-like enzymes in grey seal. Chloramphenicol (model for CYP2B) is apparently not a good inhibitor of CYP1A and CYP3A activities in grey seal because the chemical did not inhibit any metabolic route of testosterone at concentrations from 0.1 to 10 ,M. Our findings demonstrated that at least CYP1A- and CYP3A-like enzymes in the liver of grey seals are capable of metabolizing PCBs with ortho - meta and/or meta - para vicinal hydrogens. A CYP2B form might also be involved, but this could not be proven by the results of our experiments. Defining the profiles of CYP enzymes that are responsible for PCB biotransformation is necessary to fully understand the bioaccumulation, toxicokinetics, and risk of PCB exposure in seals and other free-ranging marine mammals. [source] Protective Effect of HOE642, a Selective Blocker of Na+ -H+ Exchange, Against the Development of Rigor Contracture in Rat Ventricular MyocytesEXPERIMENTAL PHYSIOLOGY, Issue 1 2000Marisol Ruiz-Meana The objective of this study was to investigate the effect of Na+ -H+ exchange (NHE) and HCO3, -Na+ symport inhibition on the development of rigor contracture. Freshly isolated adult rat cardiomyocytes were subjected to 60 min metabolic inhibition (MI) and 5 min re-energization (Rx). The effects of perfusion of HCO3, or HCO3, -free buffer with or without the NHE inhibitor HOE642 (7 ,M) were investigated during MI and Rx. In HCO3, -free conditions, HOE642 reduced the percentage of cells developing rigor during MI from 79 ± 1% to 40 ± 4% (P < 0.001) without modifying the time at which rigor appeared. This resulted in a 30% reduction of hypercontracture during Rx (P < 0.01). The presence of HCO3, abolished the protective effect of HOE642 against rigor. Cells that had developed rigor underwent hypercontracture during Rx independently of treatment allocation. Ratiofluorescence measurement demonstrated that the rise in cytosolic Ca2+ (fura-2) occurred only after the onset of rigor, and was not influenced by HOE642. NHE inhibition did not modify Na+ rise (SBFI) during MI, but exaggerated the initial fall of intracellular pH (BCEFC). In conclusion, HOE642 has a protective effect against rigor during energy deprivation, but only when HCO3, -dependent transporters are inhibited. This effect is independent of changes in cytosolic Na+ or Ca2+ concentrations. [source] Toxicity to Candida albicans mediated by human serum and peripheral blood mononuclear cellsFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 3 2006Joseph M. Bliss Abstract This study evaluates the conditions in which peripheral blood mononuclear cells mediate toxicity to Candida albicans opsonized with heat-inactivated human serum. Serum concentrations as low as 1% resulted in 50% inhibition of C. albicans metabolic activity after incubation with peripheral blood mononuclear cells at an effector to target ratio of 8. Measurable inhibition was also achieved at lower effector to target ratios and lower serum concentrations, and at least a portion of the metabolic inhibition reflected fungal cell death. Depletion of C. albicans -specific antibody decreased the toxic effect while opsonization with purified human IgG restored toxicity, and cell,cell contact between peripheral blood mononuclear cells and fungus was required. Depletion of or enrichment for monocytes from the peripheral blood mononuclear cells preparation diminished the toxic effect and the monocytic cell line, THP-1, was likewise incapable of toxicity. These studies provide evidence that antibody augments antifungal host defense and underscore the complex interrelationship between humoral and cellular immunity in these infections. [source] Few cultured rat primary sensory neurons express a tolbutamide-sensitive K+ currentJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2002Violeta Ristoiu Abstract The response of dorsal root ganglion (DRG) neurons to metabolic inhibition is known to involve calcium-activated K+ channels; in most neuronal types ATP-sensitive K+ channels (KATP) also contribute, but this is not yet established in the DRG. We have investigated the presence of a KATP current using whole-cell recordings from rat DRG neurons, classifying the neurons functionally by their "current signature" (Petruska et al, J Neurophysiol 84: 2365,2379, 2000). We clearly identified a KATP current in only 1 out of 62 neurons, probably a nociceptor. The current was activated by cyanide (2 mM NaCN) and was sensitive to 100 ,M tolbutamide; the relation between reversal potential and external K+ concentration indicated it was a K+ current. In a further two neurons, cyanide activated a K+ current that was only partially blocked by tolbutamide, which may also be an atypical KATP current. We conclude that KATP channels are expressed in normal DRG, but in very few neurons and only in nociceptors. [source] Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat modelsAGING CELL, Issue 2 2010Li-Fang Hu Summary Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H2S, a novel biological gas) on PD. The endogenous H2S level was markedly reduced in the SN in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Systemic administration of NaHS (an H2S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine-hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6-OHDA-induced PD model. H2S specifically inhibited 6-OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro-inflammatory factors (e.g. TNF-, and nitric oxide) in the striatum via NF-,B pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H2S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via multiple mechanisms including anti-oxidative stress, anti-inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD. [source] | |||||||||||||