Potentiation of the teratogenic effects of 5‐fluorouracil by natural pyrimidines. II. Biochemical aspects

Thymine (Th), uracil (U), and the antimetabolite 5‐fluorouracil (5‐FU) are metabolized in vitro by rat liver enzyme systems present in the high‐speed supernatant soluble cell fraction. The data presented demonstrate that addition of either U or Th to such preparations or the use of livers from rats pretreated intraperitoneally with U or Th markedly decreases the ability of liver preparations to metabolize 5‐FU. These findings indicate that the decreased elimination from the body of a teratogenic dose of 5‐FU after treatment with an equimolar dose of U is due to the inhibition of metabolism of the antimetabolite in the maternal liver. The concomitant administration of the natural pyrimidines Th or U with 5‐FU resulted in prolonged high serum levels of the teratogen 5‐FU, which tended to enhance transfer to and uptake by the embryo. Since the embryo was unable to dispose of 5‐FU metabolically, prolonged high levels of 5‐FU would be expected to cause increased teratogenic effects. Studies with labeled 5‐FU revealed that most of the radioactivity found in the embryos was incorporated into RNA, with only about 30% in the TCA ex tract. Concomitant treatment of pregnant rats with 5‐FU and U had greater inhibitory effect on the incorporation of formate into the methyl group of DNA thymine in the embryo than treatment with 5‐FU alone. This treatment inhibited thymidylate synthetase more than an equimolar dose of 5‐FU alone. Neither treatment affected the high kinase activity of the embryo.