Dihydropyrimidine aminohydrolase

Dexrazoxane was also hydrolyzed enzymatically in the liver and kidney by dihydropyrimidine aminohydrolase. This enzyme could hydrolyze one but not a second ring of this molecule. Levrazoxane, the enantiomer of dexrazoxane, was also hydrolyzed enzymatically by DHPase in liver homogenates, but at a rate 4.5-fold slower [136], However, in vivo studies in rats dosed with razoxane (the racemic mixture of levrazoxane and dexrazoxane) revealed only a relatively small difference in elimination of the two enantiomers. This suggests that distribution and excretion reduced the impact of stereoselective biotransformation on the pharmacokinetics of these two enantiomers [137]. 

The heterocyclic ring of hydantoins, like that of succinimides (see Sect. 4.4.2), is hydrolytically cleaved by dihydropyrimidine aminohydrolase (DHPase, EC 3.5.2.2). Since both hydantoins and succinimides are hydrolyzed by the same enzyme, it is not surprising that structural features, such as absolute configuration, ring-substitution, and TV-substitution, exhibit comparable influence on catalysis. 

The antitumor agent 5-fluorouracil (4.236) is rapidly metabolized to 2-l luoro-/ -alanine (4.237) according to the sequence depicted in Fig. 4.10 [150][151]. The degradation of 5-fluorouracil occurs in all tissues, but tumor tissues contain very small amounts of dihydropyrimidine aminohydrolase. 

DJT Porter, JA Harrington, MR Almond, GT Lowen, T Spector. (5)-5-fluoro-5,6-dihydrouracil kinetics of oxidation by dihydropyrimidine by dihydropyrimidine aminohydrolase. Biochem Pharmacol 48(4) 775—779, 1994. 

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