The study of the biological effects of foreign chemicals (whether therapeutic drugs or chemicals present at work or in the environment) interests the biologist from a number of different and complementary viewpoints. Apart from the more obvious pharmacological and toxicological interest, the experimentalist often uses foreign chemicals to produce in experimental animals disease states similar to naturally occurring diseases, so that their pathogenetic mechanisms and therapy can be studied under controlled conditions. In addition - as Claude Bernard pointed out over a century ago - foreign chemicals can be employed as instruments to analyze the most delicate vital processes; much can be learned about the physiological processes themselves by a careful study of the mechanisms by which these are altered by chemicals. The field of heme and hemoproteins offers an example of the interplay of these different approaches. Their metabolism can be altered by therapeutic drugs and other foreign chemicals and this results in a variety of biological responses that transcend the boundaries of pharmacology into the confines of clinical medi­ cine, genetics, toxicology, biochemistry and physiology. In this book a multidisciplinary approach to the study of heme metabolism is presented including the effect of chemicals on heme metabolism in patients, the results of experimental work in the whole animal, as well as in vitro studies.

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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…