Enzyme inhibitors, immunosuppressive action

CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Bruce E. Maryanoff and Cynthia A. Maryanoff. Computer Assisted Molecular Design Related to the Protein Kinase C Receptor, Paul A. Wenderand Cynthia M. Cribbs. Chemistry and Biology of the Immunosuppressant (-)-FK-506, Ichiro Shinkai and Nolan H. Sigal. The Development of Ketorolac Impact on Pyrrole Chemistry and on Pain Therapy, Joseph M. Muchowski. Application of Silicon Chemistry in the Corticosteroid Field, Douglas A. Livingston. Hu-perzine A-A Possible Lead Structure in the Treatment of Alzheimers Disease, Alan P. Kozikowski, X.C, Tang and Israel Hanin. Mechanism-Based-Dual-Action Cephalosporins, Harry A. Albrecht and James G. Christenson. Some Thoughts on Enzyme Inhibitors and the Quiescent Affinity Label Concept, Mien Krantz Index. 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

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