Rat cytochrome P450 1A and 3A enzymes involved in bioactivation of tegafurto 5-fluorouracil and autoinduced by tegafur in liver microsomes

Tegafur, an anticancer prodrug, is reported to be bioactivated to 5-fluorou racil (5-FU) by cytochrome P450 (P450) enzymes, Liver microsomal P450 enzym es involved in the biotransformation of tegafur into 5-FU in rats and the e ffect of tegafur in vivo on P450 levels in rats were investigated, Of 12 cD NA-expressed rat P450 enzymes tested, CYP1A2, CYP3A1, and CYP2C11 had high 5-FU formation rates from 100 muM and 1.0 mM tegafur concentrations, The co ntributions of CYP1A, CYP2C, and CYP3A enzymes to 5-FU formation in male ra t liver microsomes were supported by immunoinhibition studies. 5-FU formati on from tegafur, at substrate concentrations of 100 muM and 1.0 mM, was inc reased by intraperitoneal treatment of tegafur (50 mg/kg for 5 days) as wel l as by beta -naphthoflavone, phenobarbital, and dexamethasone. Orally admi nistered tegafur (100 mg/kg daily for 20 days) caused the induction of CYP2 B (5-fold) and of CYP1A and CYP3A (similar to2-fold) and of 5-FU formation (similar to2-fold) in rat liver microsomes. These results suggest that CYP1 A and CYP3A enzymes, autoinduced by tegafur, have important roles in 5-FU f ormation from tegafur in rat liver microsomes, Coadministration of tegafur and P450-inducing drugs could markedly enhance the biotransformation of teg afur into 5-FU via P450 induction.