ENZYMATIC BASIS OF CYCLOPHOSPHAMIDE ACTIVATION BY HEPATIC MICROSOMES OF THE RAT

¹ Oncology Division, Department of Medicine, Lemuel Shattuck Hospital and Tufts University School of Medicine, Boston, Massachusetts

Our data confirm and enhance the thesis that the activation of cyclophosphamide by liver is mediated through the mixed function oxidase system involved in the metabolism of drugs, steroids and carcinogens. This is based on the following lines of evidence. First, the enzyme is located primarily if not exclusively in liver microsomes. Second, the enzyme requires reduced triphosphopyridine nucleotide and molecular oxygen for full activity. Third, the enzyme is inhibited in vitro by compounds known to be metabolized by the mixed function oxidase system of liver microsomes such as hexobarbital and steroids and the kinetics of inhibition by hexobarbital is that of a competitive type. Fourth, the enzyme can be inhibited by carbon monoxide as well as other compounds known to interrupt the microsomal electron transport chain such as p-hydroxymercuribenzoate and cytochrome c. Fifth, the enzyme level is markedly increased by phenobarbital administration. Finally, there is a clear sex-related difference in concentration of this enzyme in the rat liver. Evidence is presented that the induction of cyclophosphamide-activating enzyme by phenobarbital can be correlated with an enhancement of the pharmacologic effect of cyclophosphamide in the laboratory animal.