Coumarins induction

An asymmetric induction can be performed during the cathodic reduction of various substituted coumarins in the presence of chiral alkaloids. A mixture of dimers and dihydrocoumarins is obtained in various yields according to the nature of the alkaloids (31-89% of dimer and 5-67% of dihydrocoumarin with unsubstituted coumarin) [273]. 

Reduction of coumarin in aqueous methanol, pH 5-6, in the presence of alkaloids yields an increased amount of dihydrocoumarin. Tliis is also the case for reduction of 4-methylcoumarin and now the 4-methyldihydrocoumarin isolated is optically active [137]. Tlie enantiomeric excess and yield of diliydrocompound both depend on the alkaloid used (Table 3.9) and Low concentrations of alkaloid are effective in achieving asynunetric induction. Concentrations of codeine above 4 mM do not further influence either the yield of dihydrocompound or the degree of induction. 

Certain drugs induce the hepatic microsomal enzyme system i.e. enzyme induction, which decreases the effectiveness of other drugs, for example, if phenobarbital is suddenly discontinued without lowering the dosage of coumarin, severe hemorrhage can occur. 

Coumarin did not induce micronuclei in mice in vivo and was not mutagenic in Drosophila melanogaster. It was weakly positive in induction of micronuclei in htunan cells in vitro, but failed to induce tmscheduled DNA synthesis in human liver cells in vitro. Coumarin induced sister chromatid exchanges without metabolic activation and chromosomal aberrations with metabolic activation, but not micronuclei or gene mutations in mammalian cells in vitro. It was mutagenic in only two out of 11 Salmonella typhimurium strains tested, with metabolic activation. 

Evans, J.G, Appleby, E.C., Lake, B.G Coiming, D M. (1989) Studies on the induction of cholangiofibrosis by coumarin in the rat. Toxicology, 55, 207-224 Faurschou, P. (1982) Toxic hepatitis due to benzo-pyrone. Hum. Toxicol, 1, 149-150 Fentem, J.H. Fry, J.R. (1991) Comparison of the effects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities. Xenobiotica, 21, 895-904... 

Manevich Y, Held KD, Biaglow JE (1997) Coumarin-3-carboxylic acid as a detector for hydroxyl radicals generated chemically and by gamma radiation. Radiat Res 148 580-591 Maples KR, Johnson NF (1992) Fiber-induced hydroxyl radical formation correlation with mesothelioma induction on rats and humans. Carcinogenesis 13 2035-2039 MarkG, Korth H-G, Schuchmann H-P, von Sonntag C (1996) The photochemistry of aqueous nitrate revisited. J Photochem Photobiol A Chem 101 89-103 Maskos Z, Rush JD, Koppenol WH (1990) The hydroxylation of the salicylate anion by a Fenton reaction and v-radiolysis a consideration of the respective mechanisms. Free Rad Biol Med 8 153-162... 

Olson, M.M. and Roseland, C.R., Induction of the coumarins scopoletin and ayapin in sunflower by insectfeeding stress and effects of coumarins on the feeding of sunflower beetle (Coleoptera Chrysomel-idae), Environ. Entomol., 20, 1166-1172, 1991. 

Acceleration of hepatic coumarin metabolism enzyme induction, e.g., by carbamazepine, rifampicin ... 

R. W. Wald and G. Feuer, /. Med. Chem., 14,1081 (1971). Molecular Orbital Calculations on Coumarins and the Induction of Drug-Metabolizing Enzymes. 

ANTICOAGULANTS-ORAL PHENYTOIN Possible T anticoagulant effect Possibly due to inhibition of CYP2C9-mediated metabolism of warfarin and induction of CYP1A2, which plays a role in activation of coumarins Monitor INR at least weekly until stable... 

Hamerski, D., Schmitt, D. and Matern, U. (1990) Induction of two prenyltransferases for the accumulation of coumarin phytoalexins in elicitor-treated Ammi majus cell suspension cultures. Phytochemistry, 29,1131-5. 

Electrochemical reduction of coumarin [187] affords the meso and ( ) forms of a product hydrodimerized (at C-4) like many other a,)6-unsaturated acid derivatives. In the presence of tertiary amines, which are not destroyed during the process but catalyze the evolution of hydrogen, a transfer of hydrogen takes place from the amine radical to the coumarin radical with formation of 3,4-dihydrocoumarin. Asymmetric amines cause asymmetric induction during the reduction of 4-methylcoumarin, as in Chapter 26 [188]. 

Among the coumarins isolated from species of Artemisia (Asteraceae), esculetin (6,7-dihydroxycoumarin) and its dimethyl-ether scoparone were known to be antiproliferative on vascular smooth muscle cells. This activity was further found in some very simple mono-substituted coumarins, which were even more potent than esculetin, although less effective. In an attempt to verify its mechanism of action, esculetin was tested for interactions with PTK and PKC. The induction of membrane PTK activity by either foetal calf serum or platelet-derived growth factor (PDGF) was moderately reduced by esculetin, whereas no effect was observed against PKC [56]. 

Citrus aurantium L. -laranja Nervous disturbanees Leaf (Infusion) Afro-Brazilians (Northeast Brazil) [45,46] Alkaloids [195,196] adrenergic amines [197,198] flavonoids [199,200] Coumarins, fatty acids [201,202] polyphenolic compounds [203] essential oils [204,205] Suppressive effect [267] ischemic stroke [268] cardiovascular changes [269] weight loss [267] induction of apoptosis [270] anxiolytic and sedative effects [271] adrenergic agonists [272], antiobesity [273,274] anti-inflammatory activity [275]... 

Some commercially available phenotyping kits use an array of coumarin analogs designed to be relatively isozyme-specific substrates (probes) that are metabolized to products with easily measurable spectral characteristics. Other commercially available kits use microsomes from baculovirus-infected cells that overexpress individual human GYP isoforms and fluorescent substrates (Vivid substrates) that can be incorporated into 1536 well formats. These simple systems do not readily lend themselves to the in vitro study of enzyme induction, however. The prediction of xenobiotic alteration of the expression of GYP activity in vivo from in vitro experiments will be discussed more completely in the chapter on drug—drug interactions. 

Other adverse effects Barbiturates and carbamates (but not benzodiazepines, buspirone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize dmgs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. 

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