InflammoPharmacology

, Volume 1, Issue 1, pp 3–36 | Cite as

Molecular pathology of drug-disease interactions in chronic autoimmune inflammatory diseases

  • A. L. Parke
  • C. Ioannides
  • D. F. V. Lewis
  • D. V. Parke
Article

Abstract 2

The aetiology of autoimmune, chronic inflammatory disease is reviewed, together with the contributing roles of oxygen radicals, the cytochromes P450, the eicosanoids, the interleukins, and the corticosteroids and estrogens. The importance of drug metabolism in the formation of reactive intermediates of drugs and environmental chemicals, and hence in the production of neoantigens, autoantibodies and autoimmune disease is considered, together with the possible involvement of genetic variations in sulphoxidation, sulphotransferase and acetyltransferase activities in predisposing patients to rheumatoid arthritis, lupus and other autoimmune diseases.

The toxicity of anti-inflammatory drugs, and the molecular mechanisms involved, are reviewed, including the formation of neoantigens and autoantibodies by the acylation of proteins by ester glucuronide metabolites of non-steroidal anti-inflammatory drugs, by the formation of disulphide protein conjugates of penicillamine, by theN-oxygenation of sulphonamides, and the oxygenation of hydralazine, procainamide and other drugs by leukocyte NADPH-oxidase and myeloperoxidase. The limitations of the existing procedures for the safety evaluation of new drugs, and their inability to identify potential immunotoxicity in man, are considered, and the advantages of the molecular structure procedure of COMPACT (Computer Optimised Molecular Parametric Analysis for Chemical Toxicity), and the enzyme induction procedure of ENACT (Enzyme Induction Analysis for Chemical Toxicity), for identifying potential carcinogenic and immunotoxic chemicals, are briefly discussed.

Keywords

Autoimmune disease oxygen radicals arthritis non-steroidal anti-inflammatory drugs cytochromes P450 neoantigens molecular toxicity myeloperoxidase reactive intermediates drug metabolism genetic defects in metabolism 

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© Kluwer Academic Publishers bv 1991

Authors and Affiliations

  • A. L. Parke
    • 2
  • C. Ioannides
    • 1
  • D. F. V. Lewis
    • 1
  • D. V. Parke
    • 1
  1. 1.Division of Toxicology, School of Biological SciencesUniversity of SurreyGuildford
  2. 2.Division of Rheumatology, Department of MedicineUniversity of Connecticut School of MedicineFarmingtonUSA

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