Endogenous compounds

Serotonin (12) is a ubiquitous endogenous compound that has a multitude of biological activities. For... 

Endogenous Compounds Creatinine human buffer dilution SEC SEC CIEX UV 58 ... 

The breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

Many low weight compounds produced by microor-ganism-like formylated peptides as well as endogenous mediators are chemotactic for leukocytes and promote the inflammatory process. The main endogenous compounds are listed in Table 1 and are derived from activated plasma protein cascades that function as amplification mechanisms, are performed and released from activated cells or are de novo synthesized on demand by cells participating in or being affected by inflammatory events. The major modulators of leukocyte adhesion to endothelial cells are listed in Table 2. 

Cellular defense mechanisms against toxins (A multistep mechanism for elimination of toxic metabolites and xenobiotics. It involves various transport, oxidation, and conjugation steps.) are usually divided into several steps as it is visualized on Fig. 3. Organic anion transporting proteins (OATPs) are responsible for the cellular uptake of endogenous compounds and... 

Phase II metabolism The reaction of a phase I metabolite with an endogenous compound, e.g. glucuronic acid, to form a polar compound that is eliminated from the body. 

Xenobiotic A foreign compound that has no role in the normal biochemistry of a living organism. A normal endogenous compound to one species can be a xenobiotic to another species. 

RH above can represent a very wide variety of xenobi-otics, including drugs, carcinogens, pesticides, petroleum products, and pollutants (such as a mixture of PCBs). In addition, endogenous compounds, such as certain steroids, eicosanoids, fatty acids, and retinoids, are also substrates. The substrates are generally lipophilic and are rendered more hydrophilic by hydroxy-lation. 

At least six isoforms of cytochrome P450 are present in the endoplasmic reticulum of human hver, each with wide and somewhat overlapping substrate specificities and acting on both xenobiotics and endogenous compounds. The genes for many isoforms of P450 (from both humans and animals such as the rat) have been isolated and smdied in detail in recent years. 

Involved In the metabolism of many endogenous compounds (eg, steroids)... 

Finally, derivatives of the endogenous compound 2-octyl- y-bromoacetate (65) have been reported as FAAH inhibitors [79]. In a limited SAR study, it was found that replacement of the bromine with a chlorine atom had little effect on affinity. The replacement of the alkyl chain with oleyl-chain mimics resulted in an increase of affinity for FAAH (approximately 5-fold). The removal of the halogen and replacement with either a proton or methyl resulted in inactive compounds. The most potent compound identified in this series was compound (66) with an IC50 value of 0.6/rM [79]. 

Hughes, J. Isolation of and endogenous compound from the brain with pharmacological properties similar to morphine. Rrain Res 88 295-308, 1975. 

Vogel Z, Barg R, Levy D, Saya E Eleldman, Mechoulam R. Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 1993 61 352-355. 

Owing to rapid development in analytical techniques, metabolite identification and structure elucidation have become possible even with trace levels of metabolites generated with in vitro or in vivo mammalian systems. However, the microbial bioreactor is still a valuable system for metabolite structure determination, especially when the metabolite of interest presents at a low level in in vitro or in vivo mammalian systems and the isolation from these matrices is hindered by the interference of other metabolites, the parent drug or endogenous compounds, or the structure determination requires appreciable amounts of samples due to structure complexity. 

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

Besides catalyzing styrene and benzaldehyde, CYP enzymes play an important role in the metabolism of endogenous compounds as well as in pharmacokinetics and toxicokinetics. Joseph [228] developed a biosensor with human CYP3A4 as a novel drugscreening tool. It was constructed by assembling enzyme films on Au electrodes by alternate adsorption of a layer of CYP3A4 on top of a layer of PDDA. The biosensor was applied to detect verapamil, midazolam, quinidine, and progesterone. 

The development of synthetic compounds that activate P or P2 receptors has been important for elucidating how these receptors function, because some of these compounds are more potent and selective than the parent purines, and most are more stable than the short-lived endogenous compounds adenosine and ATP. 

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