The effect of microsomal enzyme inhibition on the immunosuppressive and toxic effects of cyclophosphamide

Clin Exp Immunol. 1973 Jun;14(2):257-70.

Abstract

Cyclophosphamide is activated in vivo to toxic alkylating materials by hepatic microsomal enzymes. In mice and rats, inhibition of these enzymes by chloramphenicol or SKF 525A reduces the toxicity of cyclophosphamide but has less effect in rats and no effect in mice on its immunosuppressive activity, so increasing its therapeutic effectiveness.

In contrast, vitamin A alcohol increases cyclophosphamide toxicity, again without affecting its immunosuppressive activity.

Hepatic activation of cyclophosphamide results in the sequential appearance of several metabolites of varying toxicity. Retardation of activation by microsomal enzyme inhibitors may alter the proportions of the various metabolites present and so lead to the differential effects observed here.

Alternatively, exposure of cells to lower concentrations of active products for longer times would favour survival of cells with substantial ability to repair alkylation damage to DNA but not that of cells with little repair ability. The shape of the dose-response curve for cyclophosphamide acting on immunocytes suggests that their repair abilities are limited. The cells essential for survival, which are differentially protected against cyclophosphamide by administering microsomal enzyme inhibitors, are probably not haemopoietic stem cells but may be intestinal epithelial cells.

The clinical relevance of these experiments is discussed.

MeSH terms

  • Animals
  • Antibody Formation
  • Chloramphenicol / pharmacology
  • Cyclophosphamide / antagonists & inhibitors
  • Cyclophosphamide / toxicity*
  • Cytotoxicity Tests, Immunologic
  • Enzyme Repression
  • Immunosuppression Therapy*
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / immunology*
  • Rats
  • Sheep / immunology
  • Vitamin A / antagonists & inhibitors
  • Vitamin A / pharmacology

Substances

  • Vitamin A
  • Chloramphenicol
  • Cyclophosphamide