THEOPHYLLINE METABOLISM BY RAT-LIVER MICROSOMAL MONOOXYGENASES

The theophylline metabolism was investigated in a reconstituted monooxygenase system with highly purified forms of cytochrome P-450a, P-450b, P-450c, P-450d, and P-450k, as well as in liver microsomes of the control rats and after the administration of 3-methylcholanthrene (MC). The forms P-450a and P-450b did not exhibit activity in theophylline metabolism; P-450d and P-450k produced 1,3-dimethyluric acid (1,3-DUA) at a rate of 900 and 330 pmoles/min per nmole of cytochrome P-450, respectively. The catalytic activity of these forms was completely suppressed by homologous monospecific antibodies. P-450c catalyzed the formation of an unidentified metabolite. In the microsomes of the control animals, antibodies to cytochrome P-450k lowered the rate of formation of 1,3-DUA by 73%, while antibodies to P-450c+d decreased it by 11%. In the microsomes of MC-induced animals the rate of production of 1,3-DUA doubled. Antibodies to cytochrome P-450k inhibited 61% of this activity, while those to P-450c+d inhibited 18% of this activity.