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Vol. 49, Issue 4, 297-342, December 1997

Chemically Reactive Intermediates and Pulmonary Xenobiotic Toxicity

Theodore E. Grama

Chief, Section on Drug Interactions (retired), Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

I. Introduction
    A. Activation of Xenobiotics to Chemically Reactive Intermediates
    B. Pulmonary Cytology
II. Hyperoxic Lung Injury
    A. Effects of Hyperoxia on Survival: Gross, Microscopic, and Ultrastructural Evidence of Pathological Changes
    B. Pulmonary Enzymes That Alter Oxygen Toxicity
        1. Enzymes that promote formation of reactive oxygen species.
        2. Enzymes that catalyze inactivation of reactive oxygen species.
        3. Role of cytochrome P450 and glutathione in pulmonary oxygen toxicity.
        4. Age and species differences in the susceptibility to oxygen toxicity.
III. Paraquat and Nitrofurantoin-Induced Lung Damage
    A. Paraquat Lung Toxicity
        1. Morphological effects.
        2. Biochemical pharmacology.
    B. Nitrofurantoin Lung Injury
IV. Pulmonary Neoplasia Associated with Benzo[a]pyrene
    A. Covalent Binding of Benzo[a]pyrene to Total DNA
    B. Activation of Benzo[a]pyrene In Vivo to the Ultimate Carcinogen
    C. Stereochemistry of the Reactive Metabolite
    D. Formation of the Metabolite-DNA Adduct
    E. Mutagenicity of the Reactive Metabolite of Benzo[a]pyrene
V. Pneumotoxicity of 4-Ipomeanol and Other Furans
    A. Species Differences
    B. Covalent Binding
    C. Enzymatic Requirements for Covalent Binding: Cytochrome P450 and Glutathione
    D. Biochemical Toxicity of Methylfurans
VI. Lung Toxicity of Naphthalene and 2-Methylnapthalene
    A. Pulmonary Morphology and Monooxygenase Activities
    B. Role of Tissue Glutathione Levels: Glutathione Conjugation and Lung Toxicity
    C. The role of Stereochemistry in Naphthalene Pneumotoxicity
    D. Species Differences in Naphthalene Lung Toxicity
    E. Metabolism of Naphthalene in Purified Clara Cells from Mouse Lung
VII. Pulmonary Neoplasia Resulting from the Tobacco-Specific Nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    A. Reaction of 4-(Methylnitrosamino)-1-(3-pyridyl)1-butanone Metabolites with DNA and Persistence of the Adduct
    B. Reaction of 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone Metabolites with Specific Pulmonary Cell Types
    C. Inhibition of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Activation and Carcinogenesis
    D. The Chemical Nature of the Ultimate Carcinogenic Metabolite of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
VIII. 1,1-Dichloroethylene-Induced Lung Injury
    A. Morphological Effects in Lung and Effect on P450-Related Oxygenases
    B. Chemical Nature of the Reactive Metabolites of 1,1-Dichloroethylene
    C. Covalent Binding of 1,1-Dichloroethylene Metabolites in Tissues
    D. Role of Glutathione
    E. Role of Pulmonary P450 Isozymes in 1,1-Dichloroethylene Metabolism
IX. 3-Methylindole-Induced Lung Toxicity
    A. Morphological Evidence of Lung Damage After 3-Methylindole Administration
    B. Relationships Between Activation of 3-Methylindole in Tissues, Covalent binding, and Pulmonary Cell Necrosis
X. Butylated Hydroxytoluene and Pulmonary Toxicity
    A. Histological and Fine Structural Changes Produced by Butylated Hydroxytoluene in Lung: Incorporation of [3H]Thymidine into DNA
    B. Covalent Binding of Butylated Hydroxytoluene in Tissues, Its Amelioration, and the Nature of the Reactive Metabolite(s)
    C. Species Differences in Butylated Hydroxytoluene-Induced Lung Injury
XI. Bleomycin-Associated Lung Injury
    A. Histological and Fine Structural Changes Produced in Lung by Bleomycin
    B. The Chemical/Biochemical Mechanism by which Bleomycin Attacks DNA
    C. Biological Inactivation of Bleomycin via Bleomycin Hydrolase
    D. Strain Differences in Murine Bleomycin Effects
XII. Pulmonary Toxicology of Trialkyl Phosphorothioates (Contaminants in Malathion)
    A. Ultrastructural Changes
    B. Cytochrome P450 and Biochemical Alterations
XIII. Summary
Acknowledgments
References

a   Address correspondence to: Theodore E. Gram, 1036 Welsh Drive, Rockville, MD 20852-1202.

0031-6997/97/4904-0297$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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