Monitoring of cytochrome P-450 1A activity by determination of the urinarypattern of caffeine metabolites in Wistar and hyperbilirubinemic Gunn rats

Various studies suggest that induction of cytochrome P-450 1A (CYP1A) might be a valuable therapeutic modality for reducing the hyperbilirubinemia of infants with Crigler-Najjar syndrome type I (CNS-I), a severe form of conge nital jaundice. To evaluate inducers of CYP1A as possible tools in the trea tment of hyperbilirubinemia, a novel assay was established, based on the an alysis of the urinary pattern of caffeine metabolites in rats. Wistar rats received [1-Me-C-14]-caffeine (10 mg/kg i.p.), before and 48 h after admini stration of the potent CYP1A inducer 5,6-benzoflavone (BNF) (80 mg/kg, i.p. ). A substantial increase in the fractions of the terminal caffeine metabol ites 1-methyluric acid (1-U), I-methylxanthine (1-X), and a concomitant dec rease in the caffeine demethylation product 1.7-dimethylxanthine (1,7-X) wa s observed after application of BNF. The ratio of the caffeine metabolites (I-U + 1-X)/1.7-X may serve as an index of CYP1A activity in rats in vivo. Hyperbilirubinemic, homozygous (jj) Gunn rats are an accepted model for hum an CNS-I. In male jj Gunn rats treated with BNF or with indole-3-carbinol ( I3C, XO mg/kg, oral gavage), the inducing effect of BNF and 13C on CYP1A ac tivity was confirmed by the urinary pattern of caffeine metabolites. and wa s parallelled by a decrease in plasma bilirubin levels. These data demonstr ate the usefulness of the established caffeine assay for the evaluation of inducers of CYP1A as tools for reducing hyperbilirubinemia and further conf irm the potential Value of 13C in the treatment of CNS-I. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.