Content:
Chapter 1 Chairman's advent (pages 1–2):
Chapter 2 The function of the Drug?Metabolizing Enzymes (pages 5–24): James W. Bridges
Chapter three The impact of Inducers on Drug?Metabolizing Enzyme task and on Formation of Reactive Drug Metabolites within the Liver (pages 25–42): Sten Orrenius, Hjordis Thor and Bengt Jernstrom
Chapter four results of Inducers and Inhibitors on Drug?Metabolizing Enzymes and on Drug Toxicity in Extrahepatic Tissues (pages 43–66): Michael R. Boyd
Chapter five Induction of Enzymes considering DNA fix and Mutagenesis (pages 67–81): B. A. Bridges
Chapter 6 Induction of Drug?Metabolizing Enzymes by way of Polycyclic fragrant Hydrocarbons: Mechanisms, and a few Implications in Environmental well-being learn (pages 83–99): John R. Bend
Chapter 7 Induction of Drug?Metabolizing Enzymes by way of Phenobarbitone: Structural and Biochemical elements (pages 101–118): Urs A. Meyer, Peter J. Meier, Hans Hirsiger, Urs Giger and Felix R. Althaus
Chapter eight Substrate?Dependent Irreversible Inactivation of Cytochrome P?450: Conversion of Its Haem Moiety into converted Porphyrins (pages 119–139): Francesco De Matteis, Anthony H. Gibbs, Lavinia Cantoni and Jean Francis
Chapter nine law of Human Drug Metabolism through nutritional elements (pages 147–167): A.H. Conney, M.K. Buening, E.J. Pantuck, C.B. Pantuck, J.G. Fortner, K.E. Anderson and A. Kappas
Chapter 10 Infiuence of overseas Compounds on Formation and Disposition of Reactive Metabolites (pages 169–189): F. Oesch
Chapter eleven Pharmacokinetic elements Governing the Steady?State Concentrations of international chemical substances and Their Metabolites (pages 191–217): James R. Gillette
Chapter 12 Toxicological Implications of Polymorphic Drug Metabolism (pages 219–244): J.C. Ritchie, T.P. Sloan, J.R. Idle and R.L. Smith
Chapter thirteen Immunologically Mediated Toxicity (pages 245–259): H.E. Amos
Chapter 14 Toxicological value of Liver Hypertrophy Produced through Inducers of Drug?Metabolizing Enzymes (pages 261–274): Emmanuel Farber
Chapter 15 The impact of food and Inducers on Mechanisms of Toxicity in people and Animals (pages 275–288): Andre E.M. McLean, David J. Wltts and Denise Tame
Chapter sixteen impression of Environmental chemical substances on Drug remedy in people: reviews with Contraceptive Steroids (pages 289–306): A.M. Breckenridge, D.J. again, Karen pass, Francesca Crawford, M. MacIver, M. L'E Orme, P.H. Rowe and Eileen Smith
Chapter 17 diet D Metabolism in sufferers handled with Phenytoin and Phenobarbitone (pages 315–330): J.O. Hunter and M. Davie
Chapter 18 Chemical illness in people: difficulties in Comparative Toxicology (pages 331–347): Irving J. Selikoff
Chapter 19 Implications for destiny experiences in people (pages 349–358): John Higginson
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Additional resources for Ciba Foundation Symposium 76 - Environmental Chemicals, Enzyme Function and Human Disease
Sample text
Analysis by high-performance liquid chromatography of hydrolysed, benzo[a]pyrenemodified DNA from rat hepatocytes. (a) 2 x 108 cells, isolated from 3-methylcholanthrenetreated rats, were incubated with 90pM [jH]benzo[a]pyrene in 40 ml Krebs-Henseleit buffer for I0 min. DNA was isolated and hydrolysed to nucleosides (JernstrBm et al 1980). Hydrolysed D N A was analysed on a reversed phase column (C18) using a methanoVwater gradient. Total benzo[a]pyrene modification of cellular D N A was estimated to be 20 pmoles/mg DNA.
Schematic representation of mechanisms for metabolic activation and inactivation of environmental chemicals. ENZYME INDUCERS, DRUG METABOLISM AND TOXICITY 31 vironmental chemicals in the liver. In the example given, reactive oxygenated intermediates or free radicals are produced from non-reactive substrates by cytochrome P-450-catalysed reactions. Due to their electrophilicity, the metabolites that are formed may attack nucleophilic sites in the tissue and thereby cause cell damage. Trapping of reactive metabolites by glutathione conjugation appears to be the primary defence mechanism against the harmful effect of reactive intermediates, although the metabolism of epoxides to transdihydrodiols by epoxide hydrolase may contribute significantly to the inactivation of these species.
I also agree that covalent binding is primarily a measure of metabolism and that there is no strict correlation between covalent binding and toxicity, since toxicity probably depends on interaction with specific macromolecules. McLean: What doses of bromobenzene, paracetamol and carbon tetrachloride did you use, Professor Orrenius? Toxicity occurred within one hour, which is never found in vivo, and I wonder if your doses may be such that mechanisms quite different from those found in vivo are coming into operation.
