Search results for "Oxide"
showing 10 items of 6424 documents
Metabolic Inactivation of Reactive Metabolites
1978
ABSTRACT Many compounds which are not electrophilically reactive as such are transformed by mammalian enzymes to reactive metabolites which are, in many cases, responsible for cytotoxic, mutagenic and/or carcinogenic effects of the compounds in question. The essential role of activating systems in this situation has become common knowledge during the last decade. However, many reactive metabolites are also subject to inactivation by mammalian enzymes. This important parameter is frequently not taken into account. Compounds possessing aromatic or olefinic moieties are very widely occurring and activation of these often proceeds via an electrophilically reactive epoxide. This may be transform…
Polymerisation von äthylenoxid mit dem kaliumalkoholat von 4-benzolazo-benzylalkohol. I. Der anionische polymerisationsmechanismus
1966
Athylenoxid last sich mit dem Kaliumalkoholat von 4-Benzolazo-benzylalkohol polymerisieren. Dabei erhalten die Polyathylenoxide eine zusatzliche UV-Absorption, die auf covalent eingebaute C6H5NNC6H4(p) CH2O-Gruppen zuruckzufuhren ist. Wenn der ubliche Mechanismus der anionischen Polymerisation gilt, sollte jedes Polyathylenoxidmolekul eine besonders absorbierende Endgruppe enthalten. Fraktioniert man die mit dem Alkoholat hergestellten Polyathylenoxide, so ist die Extinktion bei gleicher Polymerkonzentration nicht wie erwartet um so groser, je kleiner das Molekulargewicht ist. Bestimmt man ferner quantitativ den Gehalt an C6H5NNC6H4(p) CH2O-Gruppen in Polyathylenoxidfraktionen und nimmt ein…
Stable Expression of Heterologous Microsomal Epoxide Hydrolase in BHK21 Cells: Influence on the Mutagenicity of Benzo[a]pyrene 4,5-Oxide
1992
Most environmental mutagens and carcinogens require metabolic activation to electro- philic intermediates capable of reacting with cellular target structures, such as DNA. These electrophilic intermediates are in addition subject to metabolic detoxification. This metabolism is mainly controlled by enzymes whose expression is very variable. Among other things, various enzymes are inducible by environmental chemicals. Understanding the toxicology of chemicals (for example, species differences, idiosyncrasias, organotropisms) therefore requires knowledge of critical host factors. One approach towards this goal involves the use of purified enzymes in metabolism and toxicological studies (Glatt …
Infiuence of Foreign Compounds on Formation and Disposition of Reactive Metabolites
2008
Many toxic compounds are unreactive and need biotransformation in order to exert their toxic effects. Several enzymes control the formation or disposition of reactive metabolites. Especially well studied is the group of enzymes responsible for the control of reactive epoxides. Such epoxides may bind spontaneously to DNA, RNA and protein. These alterations of critical cellular macromolecules may disturb the normal biochemistry of the cell and lead to cytotoxic, allergenic, mutagenic and carcinogenic effects. Whether these effects will be manifested depends on the chemical reactivity as well as on other properties (geometry, lipophilicity) of the epoxide in question. Enzymes controlling the c…
Metabolism of Chemical Carcinogens
1989
Most chemical carcinogens are chemically unreactive per se and need metabolic activation to the ultimate carcinogenic species. The enzyme pattern responsible for the generation and disposition of reactive metabolites constitutes one important early contribution to the control of chemical carcinogenesis. Especially well studied is the group of enzymes responsible for the control of reactive epoxides. Many natural as well as manmade foreign compounds, including pharmaceuticals, possess olefinic or aromatic double bonds. Such compounds can be transformed to epoxides by microsomal monooxygenases present in many mammalian organs. By virtue of their electrophilic reactivity such epoxides may spon…
Dihydrodiol Dehydrogenase: An Important Enzyme in Dihydrodiol-Epoxide Pathway — Mediated Benzo(A)Pyrene Mutagenicity
1978
Benzo(a)pyrene is metabolized to two major groups of mutagenically reactive metabolites: Monofunctional epoxides and dihydrodiol-epoxides. Various monooxygenase forms catalyze the various pathways at very different rates. In metabolic situations where the contribution by dihydrodiol-epoxides is small, epoxide hydratase represents a very efficient protective system. However, in situations where the mutagenic effect is predominately due to dihydrodiol-epoxide, the effect of epoxide hydratase is complicated and weak. We have now obtained evidence that a dihydrodiol dehydrogenase represents an efficient protective system in the latter situation. The enyzme was purified to homogeneity and the pu…
Enzymes as Regulators of Toxic Reactions by Electrophilic Metabolites
1979
Conversion of many compounds which are not electrophilically reactive as such to metabolites responsible for cytotoxic, mutagenic and/or carcinogenic effects is catalyzed by mammalian enzymes. Many reactive agents, whether metabolites or parent compounds, are also subject to inactivation by mammalian enzymes.
DRUG-DRUG INTERACTIONS VIA INHIBITION OF MICROSOMAL ENZYMES INVOLVED IN METABOLISM OF EPOXIDES PRODUCED BY MICROSOMAL MONOOXYGENASE
1977
SUMMARY Benzo(a)pyrene was activated by liver microsomes to mutagens detected by the reversion of histidine dependent Salmonella typhimurium TA 1537. Using pure epoxide hydratase or epoxide hydratase inhibitors, comparing animal species with high and low epoxide hydratase activity, or inducing monooxygenase activity, it was shown that epoxide hydratase was a critical enzyme for the inactivation of these mutagens. Many clinically used drugs are metabolized to epoxides. Epoxides are not necessarily mutagenic, but since epoxide hydratase has a very low substrate specificity, such epoxides may competitively inhibit the hydration of mutagenic epoxides, as demonstrated in the present study for th…
Role of the Well-Known Basic and Recently Discovered Acidic Glutathione S-Transferases in the Control of Genotoxic Metabolites
1991
Glutathione S-transferases (GSTs; E.C. 2. 5. 1. 18) are a family of enzymes which have increasingly attracted the interest of toxicologists, pharmacologists, biochemists and clinicians since their discovery in 1961 (1). Initially, GSTs were believed to serve as intracellular transport proteins for endogenous compounds with limited solubility in water, thus acting as an intracellular equivalent to albumin in blood plasma. In this assumed capacity of reversible binding and transport of various ligands, the corresponding protein was named ligandin (2). Following the discovery of abundant GST occurrence in most forms of aerobic life including plants, and the GST-catalysed conjugation of a wide …
Dihydrodiol Dehydrogenase: Substrate Specificity, Inducibility and Tissue Distribution
1982
The present study shows that: Dihydrodiol dehydrogenase activity is present in the 100,000 g supernatant fraction of extrahepatic tissues. Dihydrodiol dehydrogenase is able to oxidize the hydroxy group and to reduce the keto group of a number of xenobiotics including quinones derived from polycyclic aromatic hydrocarbons. Dihydrodiol dehydrogenase was not inducible by various substances including hormones, polycyclic aromatic hydrocarbons, substrates of the enzyme and potent inducers of monooxygenases, epoxide hydrolase and glutathione S-transferases. Only in the case of thyroxine was a weak induction with a high dose of the hormone observed.