Metabolic poisoning

Metabolic poisoning (O2 utilization/consumption, glycolysis, gluconeogenesis) Compensatory factors... 

Antibiotics can be classified according to their effects on the biochemistry or molecular biology of pathogens. There are ribosomal inhibitors (macrolides), cell wall disrupters 0-lactams), DNA disturbers (fluoroquinolones), and metabolic poisons (trimethoprim-sulfamethoxazole). Antibiotics also can be classified according to whether they are static (inhibitory) or cidal (lethal). The classification of drugs as either static or cidal is based on laboratory assessment of the interaction of pathogen and antibiotic drug. 

How can this enigma be answered Put away a sample of pure harmaline, with its spectral identification, onto the shelf for 50 or 100 years, and then re-analyze it Who knows, but what might be needed for this conversion is heat, or a bit of iron catalyst, or some unknown species of South American mold. Acid is certainly known to promote this oxidation. It would be very much worth while to answer this question because some, perhaps much, of the results of human pharmacological studies that involve harmaline as a metabolic poison, may be influenced by the independent action of harmine as a harmaline contaminant. 

In addn to its narcotic effects, it is a metabolic poison. It can damage the iiver to a serious degree cause death... 

Clathrin-mediated endocytosis can be blocked by several pharmacologic inhibitors, including the antipsychotic drug chlorpromazine (Thorazine), the natural product ikarugamycin, and the antiviral drug amantadine. The metabolic poisons phenylarsine oxide and sodium azide also block CMF but additionally inhibit protein synthesis. Culture of cells under conditions that deplete potassium or calcium, treatment of cells with hypertonic sucrose, or acidification of the cytoplasm by addition of... 

Only few detailed analyses of the intracellular events following epithelial injury have been performed using cells from the airways, and most mechanistic work has concentrated on pre-necrotic and necrotic processes in epitheUal cells of renal origin (Trump etal., 1980, 1981 Trump and Berezesky, 1984). Collectively these studies, which have employed a wide range of stimuli to evoke cellular injury (ischaemia, metabolic poisons, chaotropic agents and ionophores), suggest that similar patterns of intracellular events accompany injury evoked by the different stimuli. 

Both hydrogen cyanide (HCN) and hydrogen sulfide (H2S) are metabolic poisons that act in relatively similar mechanistic ways. At the cellular level, the major energy source is adenosine triphosphate (ATP). 

Formate appears to directly affect the optic nerve. It is believed that formate acts as a metabolic poison inhibiting cytochrome oxidase. The optic nerve is composed of cells that normally have low reserves of cytochrome oxidase due to their low metabolic requirements and thus may be particularly sensitive to formate-induced metabolic inhibition. 

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

Transport of newly synthesized PC from the ER to the plasma membrane. The principal site of PC synthesis is the ER and Golgi (Chapter 8). The transport of PC from its sites of synthesis to the plasma membrane has been examined using pulse-chase labeling with a [ Hjcholine precursor for PC, and rapid plasma membrane isolation with cationic beads (M. Kaplan, 1985). These studies reveal that PC transport is an extremely rapid process occurring with a 1 min (Fig. 8). This transport is unaffected by metabolic poisons that deplete cellular ATP levels, disrupt vesicle transport, or alter cytoskeletal arrangement. 

Transport of newly synthesized PC from the ER to the mitochondria. Using conventional subcellular fractionation techniques, the transport of nascent PC to the mitochondria of baby hamster kidney cells was examined by pulse-chase experiments with a [ H]choline precursor (M.P. Yaffe, 1983). These experiments show that the newly made PC pool equilibrates between the outer mitochondrial membrane and the ER in approximately 5 min (Fig. 8). Similar studies performed in yeast (G. Daum, 1986) also revealed that the PC pool rapidly equilibrates between the ER and the mitochondria. Addition of metabolic poisons did not eliminate the PC radioequilibration in yeast. Studies with isolated mitochondria demonstrate that PC loaded into the outer mitochondrial membrane can be transported to the inner membrane in an energy-independent manner (M. Lampl, 1994). Consistent with this finding is the observation that PC rapidly moves across the membrane of vesicles derived from mitochondrial outer membranes prepared ifom either mammalian cells or yeast (D. Dolis, 1996 ... 

The results indicate that the initial rate of transport of PE is rapid and proceeds without a lag (Fig. 8). The transport process is insensitive to metabolic poisons that disrupt vesicle transport and cytoskeletal structure. The rapid transport kinetics occur at rates consistent with a soluble carrier-mediated process or transfer at zones of apposition between membranes. Analysis of the kinetics of the process is complicated since only PE at the outer leaflet of the plasma membrane is measured, and the basal scramblase activity or the leakage of the ATP-dependent aminophospholipid transporter activity within the plasma membrane may be a step required for the lipid to arrive at this location. Despite these complications, the results clearly indicate that the initial rate of arrival of PE at the plasma membrane occurs on a timescale that clearly distinguishes it from well-characterized vesicle transport phenomena, and is independent of processes involved in protein transport to the cell surface. 

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