Unformatted text preview: DETOXIFICATION MECHANISMS
Dr. V. JAGADEESAN Former Deputy Director (Sr. Gr.)
FOOD AND DRUG TOXICOLOGY RESEARCH CENTRE NATIONAL INSTITUTE OF NUTRITION Indian Council of Medical Research HYDERABAD – 500 007 DETOXIFICATION MECHANISMS 1. 2. 3. What is the need ? Xenobiotics Vs Endobiotics Essential feature of detoxification Two categories of Detoxification Phase I Functionalisation Reactions 4. Act on Foreign compds. as well as endogenous substrates like fatty acids, cholesterol, bile acids, steroids Phase II Synthetic or conjugating reactions a. b. c. d. Glucuronic acid Glutathione Glycine Sulphate DM Capacity
Low at birth Ontogenic Development Depressed in old age Location Liver Skin Small Intestines Lungs Kidneys Spleen To a very little Brain extent Endoplasmic Reticulum : Microsomes MFO : Mixed Function Oxidases are those oxidations in which one atom of molecular oxygen is reduced to water while the other is incorporated into substrate. Hence mono oxygenase. Essential Requirements for MFO activity
2 : 1. Molecular O 2. NADPH 3. A flavoprotein - Cytochrome C Reductase BIOTRANSFORMATION OF XENOBIOTICS PHASE I REACTIONS
A. Oxidation Hydroxylation Epoxidation N-Dealkylation N-Oxidation Desulphuration B. C. Reduction Hydrolytic Reactions PHASE II REACTIONS
Glutathione conjugation Glucuronidation Methylation Acetylation Amino acid conjugation Thiocyanate synthesis Characteristics Reasons for diff. in biol. fate of xenobiotics Dif. In rates of absorption Differences in Differences in & transfer across cell rates of metabolism routes of entry membrane and local metab. Factors influencing xenobiotic metabolism 1. Physiological factors Sex Age Strain Genetic variation Species 2. Temporal factors Time of the day Season Circadian Rhythm 3. Environmental factors Temp. Atmosphere Organic factors : Pregnancy Disease states Hormonal imbalance Nutritional factors : Diet and Nutrition Role of nutrients in drug metabolism Proteins Apoenzymes and cell function Carbohydrates Overall cell functions Lipids Vit. A. Membrane structure Vit. E Riboflavin Flavoprotein component of Cyt P450 reduct. Niacin NADPH (essen. Cofactor) Pyridoxine heam synthesis Iron hemoprotein Copper heam synthesis (ferrochelatase) Ca, Mg, K Membrane integrity & function Effect of various Nutrients/Nutrient deficiencies on DME
Fasting Energy Protein Fat • High PUFA • Fat free diet Riboflavin Effect Observed
↓ Cyt P450 ↓ Cyt P450 & hep. MFO ↓ Cyt P450 ↑ Cyt P450 ↓ Cyt P450 ↓ Cyt P450 reductase Effect of various Nutrients/Nutrient deficiencies on DME
Vitamin C Vitamin A Vitamin E Iron Zinc Magnesium Effect Observed
↓ Cyt P450 reductase ↓ Cyt P450 reductase ↓ Cyt P450 reductase ↓ AHH,AD,MEH,UDPGT ↓ AHH,AD,MEH,UDPGT ↓ GST ↓ Cyt P450 , NADPH Oxidase ...
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This note was uploaded on 10/07/2010 for the course DBT 456 taught by Professor Ss during the Spring '10 term at Indian Institute of Technology, Guwahati.
- Spring '10