Heme and Hemoproteins

1 The Biosynthesis and Degradation of Heme.- A. Introduction.- B. Structures of Porphyrins and Hemes.- C. Function and Turnover of Hemoproteins.- D. Enzymes of Heme Biosynthesis and Degradation.- I. Outline of Pathway.- II. Aminolevulinate Synthetase (E.C. 2.3.1.37).- III. Aminolevulinate Dehydratase (E.C. 4.2.1.24).- IV. Porphobilinogen Deaminase (E.C. 4.3.1.8) and Uroporphyrinogen III Cosynthetase.- V. Uroporphyrinogen Decarboxylase (E.C. 4.1.1.37).- VI. Coproporphyrinogen Oxidase (E.C. 1.3.3.3).- VII. Protoporphyrinogen Oxidase.- VIII. Heme Synthetase (E.C. 4.99.1.1).- IX. Heme Oxygenase (E.C. 1.14.99.3).- X. Biliverdin Reductase (E.C. 1.3.1.24).- E. Conjugation of Bilirubin.- F. Control of Heme and Hemoprotein Biosynthesis.- I. Introduction.- II. Control in Erythropoietic Cells.- III. Control in Liver.- Abbreviations.- References.- 2 Induction of Hepatic Hemoproteins.- A. Introduction.- B. Use of the Term Induction in Studies on Mammalian Tissues.- C. Tryptophan Pyrrolase (Dioxygenase).- D. Cytochromes of the Endoplasmic Reticulum.- I. Cytochrome(s) P-450.- 1. Cytochrome P-450-Dependent Monooxygenase(s).- 2. Chemical Inducers.- 3. Cytochrome P-450, One Hemoprotein or Many?.- 4. Studies on the Induction Mechanism of Cytochrome P-450.- 5. Factors Influencing the Induction of Cytochrome P-450.- a) Species Differences, Genetic Factors.- b) Developmental Factors.- c) Hormonal Factors.- d) Nutritional Factors.- 6. Connection Between the Induction of Cytochrome P-450 Dependent Monooxygenase(s) and Other Effects of Inducing Agents.- a) Induction of Microsomal Enzymes and the Proliferation of Endoplasmic Reticulum Membranes.- b) General Cell Changes Induced by Treatment with Pheno-burbital.- c) Liver Growth.- 7. Reversibility of Induction Phenomena.- II. Cytochrome b5.- E. Catalase.- F. Mitochondrial Cytochromes.- G. Summary of Conclusions.- Recommended Reviews.- References.- 3 Inhibition of Liver Hemoprotein Synthesis.- A. Introduction.- B. Agents Inhibiting Heme Biosynthesis and Hepatic Hemoprotein Synthesis.- I. 3-Amino-1, 2, 4-triazole.- II. The Effect of Metals on Heme Biosynthesis.- 1. The Inhibition of Liver Heme Synthesis by Cobalt.- 2. Effect of Manganese and Cadmium.- III. Role of Agents Which Affect the Availability of Glycine.- IV. Effect of Acetate on Heme Biosynthesis.- C. Conclusions.- Abbreviations.- References.- 4 Loss of Liver Cytochrome P-450 Caused by Chemicals. Damage to the Apoprotein and Degradation of the Heme Moiety.- A. Introduction.- B. Loss of Liver Cytochrome P-450 Caused by Chemicals Which Require Metabolic Conversion to Reactive Derivatives.- I. 2-Allyl-2-isopropylacetamide and Related Drugs.- 1. Loss of Pre-existing Cytochrome P-450.- 2. Conversion of Heme into Unidentified “Green Pigments”.- 3. Importance of the Allyl Group and Role of the Drug-Metabolizing Activity of the Liver.- 4. Possible Mechanisms Underlying the Loss of Heme.- II. Carbon Disulphide and Other Sulphur-Containing Chemicals.- 1. Oxidative Desulphuration of CS2.- 2. Loss of Cytochrome P-450 During Oxidative Desulphuration of Parathion and of Other Sulphur-Containing Chemicals. Liver Toxicity of Phosphorothionates.- 3. Possible Mechanisms Underlying the Loss of Cytochrome P-450 Caused by Sulphur-Containing Chemicals. Nature of the Primary Target Within the Hemoprotein.- III. Loss of Cytochrome P-450 Heme Caused by Carbon Tetrachloride in Rat Liver.- C. Increased Breakdown of the Heme of Liver Cytochrome P-450 Associated with Lipid Peroxidation.- I. Lipid Peroxidation in vitro.- II. Lipid Peroxidation in vivo.- III. Mechanisms Underlying the Production and Decomposition of Lipid Peroxides and the Associated Destruction of Heme.- D. Loss of Liver Cytochrome P-450 Caused by the Administration of Various Metals.- I. Increased Rate of Liver Heme Turnover and Stimulation of Heme Oxygenase.- II. Other Experimental Conditions Where Stimulation of Heme Oxygenase is Seen in Association with Decreased Levels of Cytochrome P-450.- III. Possible Mechanisms by Which Loss of Cytochrome P-450 and Stimulation of Heme Oxygenase may be Related.- 1. The Heme of Cytochrome P-450 as an Inducer for Heme Oxygenase.- 2. The Heme of Cytochrome P-450 as a Substrate for Heme Oxygenase.- Abbreviations.- References.- 5 Hepatic Porphyrias Caused by 2-Allyl-2-isopropylacetamide, 3,5-Diethoxycarbonyl-1,4-dihydrocollidine, Griseofulvin and Related Compounds.- A. Introduction.- I. The Concept of Porphyria.- II. Drugs and Liver Porphyrin Metabolism: Two Types of Interaction.- III. The Induction of Porphyria by Drugs in the Normal Liver.- B. The Mechanism of Induction of Porphyria by Drugs.- I. Stimulation of 5-Aminoevulinate Synthetase (ALA-S).- 1. Interference by Drugs with the Regulation of the Pathway Through Loss of Liver Heme. The “Specific” Effect.- a) Increased Destruction of Liver Heme Caused by Allyl-Con-taining Acetamides and Barbiturates.- b) Inhibition of Liver Heme Synthesis Caused by DDC and Griseofulvin.- c) Requirement for Specific Chemical Structures.- d) Heme Pools Depleted in Porphyria. Importance of Heme with Rapid Turnover.- 2. The Action Related to the Property of Lipid Solubility of Drugs. The Nonspecific Effect in the Stimulation of ALA-S.- a) Drug Interactions in Experimental Porphyria.- b) Possible Mechanisms Underlying the Nonspecific Effect.- 3. Possible Role of Drug Metabolism and of Protein Synthesis in the Stimulation of ALA-S Caused by Drugs.- Abbreviations.- References.- 6 Porphyria Caused by Hexachlorobenzene and Other Polyhalogenated Aromatic Hydrocarbons..- A. Introduction.- B. Properties and Metabolism of Porphyrogenic Polyhalogenated Aromatic Hydrocarbons.- I. Chemistry and Nomenclature.- II. Absorption, Distribution in the Body, Metabolism and Excretion.- 1. Hexachlorobenzene.- a) Absorption and Distribution.- b) Metabolism and Excretion.- 2. Other Porphyrogenic Polychlorinated Aromatic Hydrocarbons.- C. Porphyria Caused by Hexachlorobenzene and Other Halogenated Aromatic Hydrocarbons.- I. Hexachlorobenzene.- 1. HCB Porphyria in Man.- a) Clinical Features.- b) Biochemical Features.- c) Porphyria due to Occupational Exposure to HCB.- 2. HCB Porphyria in the Rat.- a) General Features.- b) Porphyrins in Urine, Faeces and Tissues.- c) Factors Influencing the Porphyrogenic Action of HCB in Rats.- 3. HCB Porphyria in Other Species.- a) Mammals.- b) Birds.- II. Other Polyhalogenated Aromatic Hydrocarbons.- 1. Polyhalogenated Biphenyls.- 2. Porphyria Associated with the Manufacture of Chlorinated Phenols: TCDD.- a) Porphyria in Herbicide Factories.- b) TCDD.- 3. Other Halogenated Aromatic Compounds.- III. Conclusion.- D. The Effect of Polyhalogenated Aromatic Hydrocarbons on Heme Metabolism in the Liver.- I. Effect on Hemoproteins in the Liver.- 1. Microsomal Hemoproteins.- 2. Other Hemoproteins.- II. Effect on Enzymes of the Heme Biosynthetic Pathway.- 1. 5-Aminolaevulinate Synthetase (ALA-S).- 2. Uroporphyrinogen Decarboxylase (UROG-D).- 3. Coproporphyrinogen Oxidase (CPG-OX).- 4. Other Enzymes.- 5. Conclusion.- E. The Mechanism of the Porphyrogenic Action of Polyhalogenated Aromatic Hydrocarbons.- I. The Mechanism of the Delayed Response to the Porphyrogenic Action of Polyhalogenated Aromatic Hydrocarbons.- II. The Relationship Between Porphyria and Morphological Changes in the Liver.- III. Inhibition of UROG-D by Porphyrogenic Compounds or Their Metabolites.- IV. The Role of Iron in the Production of Porphyria.- F. General Conclusions.- Abbreviations.- References.- 7 The Effect of Chemicals on Hepatic Heme Biosynthesis. Differences in Response to Porphyrin-Inducing Chemicals Between Chick Embryo Liver Cells, the 17-Day-Old Chick Embryo and Other Species..- A. Introduction.- B. Porphyrin Induction in Chick Embryo Liver Cells.- 1. Structure-Activity Relationships.- 2. Pattern of Porphyrin Accumulation.- 3. Mechanism of Action of Porphyrin-Inducing Drugs.- C. Porphyrin Induction in 17-Day-Old Chick Embryos.- D. Porphyrin Induction in Chickens and Japanese Quail.- E. Differences in Response to Porphyrin-Inducing Drugs in Different Species and Model Test Systems.- 1. Comparison of Response in Chick Embryo and Rat Liver Cells in Culture.- 2. Comparison of Response in Chick Embryo Liver Cells in Culture with the Response of the 17-Day-Old Chick Embryo.- 3. Comparison of Responsiveness of 17-Day-Old Chick Embryo and the Chicken.- 4. Comparison of Responsiveness of Avian and Mammalian Species.- 5. Extrapolation of Results from Animal and Model Test Systems to Man.- Abbreviations.- References.- 8 Pharmacogenetics in the Field of Heme Metabolism: Drug Sensitivity in Hereditary Hepatic Porphyria..- A. Hereditary Hepatic Porphyrias.- I. Enzyme Defects in the Hepatic Porphyrias.- 1. Intermittent Acute Porphyria (IAP).- 2. Hereditary Coproporphyria (HCP).- 3. Variegate Porphyria (VP).- 4. Porphyria Cutanea Tarda (PCT).- II. Biochemical Basis for Clinical Features in the Hepatic Porphyrias.- B. Precipitation of Hereditary Hepatic Porphyria by Drugs.- C. Experimental Models for the Exacerbation of Hereditary Hepatic Porphyria by Drugs.- D. Common Basis for Induction of Hepatic ALA-Synthetase in Clinical and Experimental Porphyria.- References.- 9 The Influence of Hormonal and Nutritional Factors on the Regulation of Liver Heme Biosynthesis..- A. Introduction.- B. The Influence of Nutritional Factors.- I. Carbohydrates and Protein.- 1. The “Glucose Effect” in Experimental Porphyria.- 2. The “Glucose Effect” in Human Hepatic Porphyria.- 3. Possible Mechanisms Underlying the “Glucose Effect”.- II. Other Dietary Factors.- C. The Influence of Hormonal Factors.- References.- 10 Effects of Drugs on Bilirubin Metabolism..- Definition of Certain Abnormalities of Bilirubin Metabolism.- A. Introduction.- B. Normal Bilirubin Metabolism.- I. Sources of Bilirubin.- II. Enzymatic Degradation of Heme.- III. Albumin Binding of Bilirubin.- IV. Hepatocellular Uptake.- V. Intracellular Binding.- VI. Conjugation of Bilirubin.- VII. Excretion to Bile.- VIII. Intestinal Fate of Bilirubin.- C. Drug-Mediated Alterations in Bilirubin Metabolism.- I. Increased Bilirubin Production Due to Erythrocyte Destruction.- 1. Hemolysis Related to Impaired Erythrocyte Metabolism.- 2. Hemolysis and Unstable Hemoglobins.- 3. Drug-Induced Immune Hemolysis.- II. Effect of Drugs on Hepatic Hemoprotein Turnover.- 1. Drugs and Bilirubin Production.- 2. Drugs and Heme Oxygenase.- 3. Heme Catabolism in Drug-Induced Porphyria.- III. Drugs and Protein Binding of Bilirubin.- Binding Capacity of Neonatal Albumin.- IV. Drugs and the Hepatocellular Uptake and Storage of Bilirubin.- 1. Interference with Transport of Bilirubin Across Membranes.- 2. Interference with Cytoplasmic Binding of Bilirubin.- 3. Drug-Mediated Increases in Bilirubin Uptake and Storage.- V. Drugs and the Glucuronyl Transferases.- 1. Glucuronyl Transferase Assay Techniques.- 2. Glucuronyl Transferase Induction.- a) Phenobarbital.- b) Glutethimide.- c) Antipyrine.- d) Dicophane (DDT).- e) Clofibrate.- f) Other Agents.- g) GT Induction in Animals.- 3. Glucuronyl Transferase Inhibition.- a) Novobiocin.- b) Vitamin K.- c) Other Agents.- d) GT Inhibition in Intact Cells.- 4. Alterations in UDP-Glucuronic Acid Availability.- VI. Drugs and the Biliary Excretion of Bilirubin.- 1. Drugs Increasing Bilirubin Excretion.- 2. Drugs Decreasing Bilirubin Excretion.- 3. Cholestasis Due to Drugs.- 4. Phenobarbital Therapy of Cholestasis.- VII. Drugs and Bilirubin in the Intestine.- VIII. Alternate Paths of Bilirubin Excretion.- IX. Bilirubin Photodegradation.- Abbreviations.- References.- 11 Toxic Effects of Lead, with Particular Reference to Porphyrin and Heme Metabolism..- A. Biosynthesis of Heme.- I. Conversion of ALA to Porphobilinogen (PBG).- II. Conversion of PBG to Uroporphyrinogen III.- III. Formation of Protoporphyrin IX.- IV. Formation of Heme.- B. Effect of Lead on the Heme Biosynthetic Pathway.- I. Inhibition of ALA-Dehydratase (ALA-D) Activity.- 1. Assay of ALA-D Activity.- 2. Inhibition Kinetics.- 3. Genetic Factors Which Affect ALA-D Levels.- 4. Erythrocyte GSH Concentration in Lead Poisoning.- II. Inhibition of Ferrochelatase.- 1. Assay of Erythrocyte Proporphyrin.- 2. Increased Protoporphyrin is Chelated with Zinc.- III. Effects of Lead on ALA-Synthetase.- IV. Effects on Other Enzymes of the Heme Biosynthetic Pathway.- V. Effect of Lead on Heme Degradation.- C. Toxic Effects of Exposure to Lead.- I. Effect on the Red Blood Cells.- 1. Distribution of Lead Between Red Cells and Plasma.- 2. Effect of Lead on Globin Synthesis.- 3. Fast Hemoglobin.- 4. Basophilic Stippling of Erythrocytes in Lead Poisoning.- 5. Effects of Lead on Mitochondria.- 6. Anemia in Lead Poisoning.- II. Lead Effect on the Immune System.- III. Drug Metabolizing System.- IV. Lead Neuropathy.- 1. Encephalopathy.- 2. Neuropathy in Lead Poisoning and in Acute Intermittent Porphyria.- V. Lead Effects on the Kidney.- VI. Tumorigenic and Teratogenic Effects of Lead.- D. Biological Defense Mechanisms Against Lead.- E. Factors Affecting the Toxic Effects of Lead.- I. Alcohol.- II. Sickle Cell Anemia.- III. Diet.- IV. Iron Deficiency.- F. Diagnosis of Lead Poisoning.- G. Summary.- Abbreviations.- References.- Author Index.