Inhibition synthesis

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

Bradykinin stimulates natriuresis and, through stimulation of prostaglandin synthesis, inhibits the actions of antidiuretic hormone (ADH), thereby inhibiting water retention. Bradykinin further improves insulin sensitivity and cellular glucose utilization of skeletal muscle cells in experimental models. This, however, appears not to be relevant in the clinical context. 

The active metabolite of leflunomide, the ring-opened drug A771726, inhibits dihydroorotate dehydrogenase (DHOD) which is the key enzyme of the de novo pyrimidine synthesis. Inhibition of synthesis stops proliferation of activated lymphocytes. The leflunomide derivative FK778 which shows similar therapeutic efficacy but shorter half-life is investigated in clinical trials. 

Other, more general effects of insulin on cellular function include stimulation of cell growth (increase in DNA and protein synthesis), inhibition of apoptosis, and modulation of ion-channel activity. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Pryor GT Persisting neurotoxic consequences of solvent abuse a developing animal modelfortoluene-inducedneurotoxicity. NlDAResMonogr 101 136—166,1990 Pudiak CM, Bozarth MA The effect of nitric oxide synthesis inhibition on intravenous cocaine self-administration. Prog Neuropsychopharmacol Biol Psychiatry 26 189— 196, 2002... 

Bacterial cell wall j3-Lactams Glyoopeptides Cycloserine Isoniazid Ethambutol Inhibit peptidoglycan synthesis Inhibit peptidoglycan synthesis Inhibits peptidoglycan synthesis Inhibits mycolic acid synthesis Inhibits arabinogalactan synthesis None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells... 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Cytoplasmic membrane Polymyxins Polyenes Imidazoles and triazoles Naftidine Disrupt bacterial membranes Disrupt fungal membranes Inhibit ergosterol synthesis Inhibits ergosterol synthesis Bind to LPS and phospholipids Bind preferentially to ergosterol Pathway not in mammalian cells Pathway not in mammalian cells... 

Metyrapone synthesis. Inhibits 11 -hydroxylase. 750 mg/day than 600 mg/day). Generally well tolerated. patients with hyperlipidemia. Used in Cushing s disease, ectopic... 

Mycophenolate mofetil was approved by the FDA in 1995, and enteric-coated mycophenolic acid was approved in 2004. Both agents are considered to be adjunctive immunosuppressants. Mycophenolic acid acts by inhibiting inosine monophosphate deydrogenase, a vital enzyme in the de novo pathway of purine synthesis. Inhibition of this enzyme prevents the proliferation of most cells that are dependent on the de novo pathway for purine synthesis, including T cells.7,11,26-28... 

Clarke, H. J., and Masui, Y. (1983). The induction of reversible and irreversible chromosome decondensation by protein synthesis inhibition during meiotic maturation of mouse oocytes. Dev. Biol. 97 291-301. 

Kapas, L., Fang, J. 8r Krueger, J. M. (1994a). Inhibition of nitric oxide synthesis inhibits rat sleep. Brain Res. 664, 189-96. 

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of (3 oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down (3 oxidation (Fig. 13-5). 

Azcona-Olivera, J. I. et al. Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol) Relationship to toxin distribution and protein synthesis inhibition. Toxicol. Appl. Pharmacol. 133, 109, 1995. 

Froscio SM, Humpage AR, Burcham PC, Falconer IR (2003) Cylindrospermopsin-induced protein synthesis inhibition and its dissociation from acute toxicity in mouse hepatocytes. Environ Toxicol 18 243-251... 

Eukaryotic organisms HeLa cells DNA synthesis inhibition - - Painter and Howard 1982 KCN... 

Only one in vivo study was located. No testicular DNA-synthesis inhibition was detected in mice after a single oral dose of 1 mg/kg cyanide as potassium cyanide (Friedman and Staub 1976). The results indicate that cyanide, especially in a form of salts, is not mutagenic. 

Painter RB, Howard R. 1982. The HeLa DNA-synthesis inhibition test as a rapid screen for mutagenic carcinogens. Mutat Res 92 427-437. 

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