Cytochrome P-450-Dependent Oxidative Cleavage of 1-(Tetrahydro-2-Furanyl)-5-Fluorouracil to 5-Fluorouracil

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Abstract
Cytochrome P-450-dependent oxidative cleavage of 1-(tetrahydro-2-furanyl)-5-fluorouracil [antineoplastic agent] (FT) was investigated in a reconstituted system containing purified phenobarbital-inducible cytochrome P-450 (P-4501) or 3-methylcholanthrene-inducible cytochrome P-450 (P-4481). FT was converted into 5-fluorouracil (5-FU) in the reconstituted system, and its rate was 71 pmol 5-FU formed/min per nmol P-4501 and 45 pmol 5-FU/min per nmol P-4481. Cytochrome P-450, NADPH-cytochrome P-450 reductase and NADPH were required for 5-FU production. Inhibitors of cytochrome P-450 such as CO and metyrapone markedly decreased the rate. FT interacted with the purified cytochrome P-450, causing a reverse type I spectral change. The hepatic microsomal cytochrome P-450-dependent mixed function oxidase system participates in the oxidative cleavage of FT.