Enzyme/transporter inducer

Each term with a metabolic component (Fgm, Fh, CL) is a function of unbound fraction in blood (/ ) and intrinsic clearance (i.e., Emax/Km in biochemical terms) and can be modified by an enzyme/transporter inducer or inhibitor. If chug is completely absorbed and elimination occurs exclusively in the liver, the systemic AUC observed in the presence of a metabolic modulator would directly reflect... 

Lipoprotein (LPLase) is required for the metabolism of both chylomicrons and VLDL. This enzyme is induced by insulin and transported to the luminal surface of capillary endothelium where it is in direct contact with the blood. Lipoprotein lipase hydrolyzes the fiitty adds from triglycerides carried by ch)4oinicrons and VLDL and is activated by apoC-II. 

An experimental protocol designed to detect and characterize isoenzyme mechanisms (that is, enzyme mechanisms requiring one or more isomerization steps of the free enzyme before the catalytic cycle is completed) . In iso mechanisms, the substrate and product bind to two different conformational forms of the enzyme. The induced transport approach requires preincubation of both labeled substrate and labeled product with enzyme, allowing the system to reach equilibrium a large amount of unlabeled substrate is then added. If an iso step is... 

Dixit, V., Hariparsad, N., Li, F., Desai, P., Thummel, K. E., and Unadkat, J. D. (2007) Cytochrome P450 enzymes and transporters induced by anti-HIV protease inhibitors in human hepatocytes implications for predicting clinical drug interactions. Drug Metab. Dispos. 35, 1853-1859. 

The conformational coupling hypothesis (1974) proposed that the free energy released from electrons during transport induced conformational change in the enzyme mediated by certain membrane proteins, to enhance its affinity for substrates. Appositely positioned substrates readily undergo dehydration to form ATP which remains enzyme-bound until pertinent energy-induced conformational change promotes its release. However, the membrane proteins remain unidentified. 

CCK is found in the digestive tract and the central and peripheral nervous systems. In the brain, CCK coexists with DA. In the peripheral nervous system, the two principal physiological actions of CCK are stimulation of gaU. bladder contraction and pancreatic enzyme secretion. CCK also stimulates glucose and amino acid transport, protein and DNA synthesis, and pancreatic hormone secretion. In the CNS, CCK induces hypothermia, analgesia, hyperglycemia, stimulation of pituitary hormone release, and a decrease in exploratory behavior. The CCK family of neuropeptides has been impHcated in anxiety and panic disorders, psychoses, satiety, and gastric acid and pancreatic enzyme secretions. 

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

---