Metabolite binding proteins

M12. Morey, K. S., and Litwack, G., Isolation and properties of cortisol metabolite binding proteins of rat liver cytosol. Biochemistry 8, 4813-4821 (1969). 

Keywords Enzymes Liquid chromatography-mass spectrometry (LC-MS) Metabolite binding proteins Metabolomics... 

The working hypothesis is that, by some means, interaction of an allosteric enzyme with effectors alters the distribution of conformational possibilities or subunit interactions available to the enzyme. That is, the regulatory effects exerted on the enzyme s activity are achieved by conformational changes occurring in the protein when effector metabolites bind. 

Axelrod, J., Burch, R. M. and Jelsema, C. L. Receptor-mediated activation of phospholipase A2 via GTP-binding proteins arachidonic acid and its metabolites as second messengers. Trends Neurosci. 11 117-123,1988. 

Male rats are sensitive to renal tubular nephropathy after exposure to hexachloroethane. The lesions observed are characteristic of hyaline droplet nephropathy. They are most likely the result of hexachloroethane or one of its metabolites binding to the excretory protein 2p-globulin, altering its kidney transport, and leading to the formation of hyaline droplets. This protein is synthesized by male rats and accounts for 26% of their urinary protein excretion (Olson et al. 1990). It is not excreted in female rats except in minimal quantities. Since some effects are also seen in kidneys of female rats and in male and female mice that do not synthesize 2p-globulin, hexachloroethane must also have milder adverse effects on the kidney through a different mechanism. 

Type IV Delayed-type Hypersensitivity (DTH). Delayed-type hypersensitivity reactions are T-cell mediated with no involvement of antibodies. However, these reactions are controlled through accessory cells, suppressor T cells, and monokine-secreting macrophages, which regulate the proliferation and differentiation of T cells. The most frequent form of DTH manifests itself as contact dermatitis. The drug or metabolite binds to a protein in the skin or the Langerhans cell membrane... 

The upshot of these points is that it may not be practical to follow established guidelines for ADME evaluation. Binding proteins, immunoreactive metabolites and antibodies could interfere with the immunoassays used to measure the activity of biotechnologically derived pharmaceuticals. The link between immunoreactivity and... 

A recent in vitro study of mice hepatic microsomes indicated that a reductive pathway may also play an important role in chloroform hepatotoxicity (Testai et al. 1990). It was demonstrated that radical chloroform metabolites bind to macromolecules (proteins, lipids) and the process can be inhibited by reduced GSH. 

Absorption/Distribution - Clopidogrel absorption is 50% or more and is rapid after oral administration. Bioavailability is unaffected by food. Both the parent compound and the main metabolite bind reversibly in vitro to plasma protein (98% and 94%, respectively). 

Ju, C. andUetrecht, J.P. (2002) Mechanism of idiosyncratic drug reactions reactive metabolites formation, protein binding and the regulation of the immune system. Current Drug Metabolism, 3, 367-377. 

Fluorination of the vitamin D3 side chain was anticipated to have an impact on its metabolism pathway. 26,27-Hexafluorocalcitriol, faiecaicitrioi, was found to be several times more potent than caicitrioi in the regulation of Ca metabolism and of the immune system. The reason for this higher biological activity has been attributed to several mechanisms a higher activity of its 23(5)-hydroxylated metabolite [26,27-hexafluoro-l,23(5),25(OH)3D3], a lower affinity of faiecaicitrioi for the vitamin D binding protein and a higher affinity of falecalcitriol-... 

It is highly bound to plasma protein (90% to 95%). The major binding protein is ttj-acid glycoprotein. Plasma half life is 3 to 6 hrs, and excreted through urine (95%) breast milk 5% in faeces as glucuronide metabolites. 

Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional up to 800 mg orally. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. There are no active metabolites and protein binding is minimal. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are negligible. 

Vitamin D and its metabolites circulate in plasma tightly bound to a carrier protein, the vitamin D-binding protein. This .-globulin binds 25(OH)D and 24,25(OH)2D with comparable high affinity and vitamin D and l,25(OH)2D with lower affinity. 

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

Patients with nephrotic syndrome can lose vitamin D metabolites in the urine, presumably by loss of the vitamin D-binding protein. Such patients may have very low 25(OH)D levels. Some of them develop bone disease. It is not yet clear what value vitamin D therapy has in such patients, because therapeutic trials with vitamin D (or any other vitamin D metabolite) have not yet been carried out. Because the problem is not related to vitamin D metabolism, one would not anticipate any advantage in using the more expensive vitamin D metabolites in place of vitamin D itself. 

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