Conjugation Reaction (conjugation + reaction)

Distribution by Scientific Domains

Selected Abstracts

The Biochemistry of Drug Metabolism , An Introduction


Abstract This paper reviews the general principles and concepts underlying Drug and Xenobiotic Metabolism. Its five Chapters deal with: 1.1. Drugs and Xenobiotics, 1.2. What are Drug Disposition and Metabolism?, 1.3. Where does Drug Metabolism Occur?, 1.4. Consequences of Drug Metabolism -- An Overview, and 1.5. Drug Metabolism and Drug Discovery. This review is the first of seven Parts which will be published at intervals. The subsequent Parts will cover: 2. Redox Reactions and Their Enzymes, 3. Reactions of Hydrolysis and Their Enzymes, 4. Conjugation Reactions and Their Enzymes, 5. Metabolism and Bioactivity, 6. Inter-Individual Factors Affecting Drug Metabolism, and 7. Intra-Individual Factors Affecting Drug Metabolism. [source]

Study of in vitro glucuronidation of hydroxyquinolines with bovine liver microsomes

Masanobu Kanou
Abstract Glucuronidation of drugs by UDP-glucuronosyltransferase (UGT) is a major phase II conjugation reaction. Defects in UGT are associated with Crigler,Najjar syndrome and Gilbert's syndrome with severe hyperbilirubinaemias and jaundice. We analysed the reactivities of some hydroxyquinoline derivatives, which are naturally produced from quinoline by cytochrome P450. The analyses were carried out using a microassay system for UGT activity in bovine liver microsomes in the range 0.5,100 pmol/assay with the highly sensitive radio-image analyser Fuji BAS2500 (Fujifilm, Tokyo, Japan). 3-Hydroxylquinoline is a good substrate for glucuronidation, and the relative Kcat values were 3.1-fold higher than the values for p-nitrophenol. 5,6-Dihydroquinoline-5,6- trans -diol gave a similar Km value to that of 3-hydroxyquinoline, but the Vmax value was approximately 1/15 of that of p-nitrophenol and showed weak reactivity. Quinoline N-oxide gave a low Vmax value and showed marginal activity. The Kcat values of 6-hydroxyquinoline and 5-hydroxyquinoline were 2.1- and 1.2-fold higher than that of p-nitrophenol, respectively. Fluoroquinoline (FQ) derivatives, such as 3FQ, 7,8diFQ and 6,7,8triFQ, did not show any substrate activities. These results suggest that there are therapeutic problems in administration of some quinoline drugs to patients with jaundice. [source]

Mass spectrometry of steroid glucuronide conjugates.

-diol 3-, -steroid-, -steroid-17- O -, 17-glucuronides, 3-keto-, Electron impact fragmentation of 3-keto-4-en-, glucuronides
Abstract The steroid glucuronide conjugates of 16,16,17-d3 -testosterone, epitestosterone, nandrolone (19-nortestosterone), 16,16,17-d3 -nortestosterone, methyltestosterone, metenolone, mesterolone, 5,-androstane-3,,17,-diol, 2,2,3,4,4-d5 -5,-androstane-3,,17,-diol, 19-nor-5,-androstane-3,,17,-diol, 2,2,4,4-d4 -19-nor-5,-androstane-3,,17,-diol and 1,-methyl-5,-androstane-3,/,,17,-diol were synthesized by means of the Koenigs,Knorr reaction. Selective 3- or 17- O -conjugation of bis-hydroxylated steroids was performed either by glucuronidation of the corresponding steroid ketole and subsequent reduction of the keto group or via a four-step synthesis starting from a mono-hydroxylated steroid including (a) protection of the hydroxy group, (b) reduction of the keto group, (c) conjugation reaction and (d) removal of protecting groups. The mass spectra and fragmentation patterns of all glucuronide conjugates were compared with those of the commercially available testosterone glucuronide and their characterization was performed by gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. For mass spectrometry the substances were derivatized to methyl esters followed by trimethylsilylation of hydroxy groups and to pertrimethylsilylated products using labelled and unlabelled trimethylsilylating agents. The resulting electron ionization mass spectra obtained by GC/MS quadrupole and ion trap instruments, full scan and selected reaction monitoring experiments are discussed, common and individual fragment ions are described and their origins are proposed. Copyright 2001 John Wiley & Sons, Ltd. [source]

Insect glutathione transferases and insecticide resistance

A. A. Enayati
Abstract Glutathione transferases (GSTs) are a diverse family of enzymes found ubiquitously in aerobic organisms. They play a central role in the detoxification of both endogenous and xenobiotic compounds and are also involved in intracellular transport, biosynthesis of hormones and protection against oxidative stress. Interest in insect GSTs has primarily focused on their role in insecticide resistance. GSTs can metabolize insecticides by facilitating their reductive dehydrochlorination or by conjugation reactions with reduced glutathione, to produce water-soluble metabolites that are more readily excreted. In addition, they contribute to the removal of toxic oxygen free radical species produced through the action of pesticides. Annotation of the Anopheles gambiae and Drosophila melanogaster genomes has revealed the full extent of this enzyme family in insects. This mini review describes the insect GST enzyme family, focusing specifically on their role in conferring insecticide resistance. [source]

In vitro metabolism of , -lapachone (ARQ 501) in mammalian hepatocytes and cultured human cells

Xiu-Sheng Miao
ARQ 501 (3,4-dihydro-2,2-dimethyl-2H -naphthol[1,2-b]pyran-5,6-dione, , -lapachone) is an anticancer agent, currently in multiple phase II clinical trials as monotherapy and in combination with other cytotoxic drugs. This study focuses on in vitro metabolism in cryopreserved hepatocytes from mice, rats, dogs and humans using [14C]-labeled ARQ 501. Metabolite profiles were characterized using liquid chromatography/mass spectrometry combined with an accurate radioactivity counter. Ion trap mass spectrometry was employed for further structural elucidation. A total of twelve metabolites were detected in the mammalian hepatocytes studied; all of which but one were generated from phase II conjugation reactions. Ten of the observed metabolites were produced by conjugations occurring at the reduced ortho -quinone carbonyl groups of ARQ 501. The metabolite profiles revealed that glucuronidation was the major biotransformation pathway in mouse and human hepatocytes. Monosulfation was the major pathway in dog, while, in rat, it appears glucuronidation and sulfation pathways contributed equally. Three major metabolites were found in rats: monoglucuronide M1, monosulfate M6, and glucuronide-sulfate M9. Two types of diconjugation metabolites were formed by attachment of the second glycone to an adjacent hydroxyl or to an existing glycone. Of the diconjugation metabolites, glucosylsulfate M10, diglucuronide M5, and glucuronide-glucoside M11 represent rarely observed phase II metabolites in mammals. The only unconjugated metabolite was generated through hydrolysis and was observed in rat, dog and human hepatocytes. ARQ 501 appeared less stable in human hepatocytes than in those of other species. To further elucidate the metabolism of ARQ 501 in extrahepatic sites, its metabolism in human kidney, lung and intestine cells was also studied, and only monoglucuronide M1 was observed in all the cell types examined. Copyright 2008 John Wiley & Sons, Ltd. [source]