Monitoring of cytochrome P-450 1A activity by determination of the urinary pattern 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 congenital jaundice. To evaluate inducers of CYP1A as possible tools in the treatment of hyperbilirubinemia, a novel assay was established, based on the analysis of the urinary pattern of caffeine metabolites in rats. Wistar rats received [1-Me-(14)C]-caffeine (10 mg/kg i.p.), before and 48h after administration of the potent CYP1A inducer 5,6-benzoflavone (BNF) (80 mg/kg, i.p.). A substantial increase in the fractions of the terminal caffeine metabolites 1-methyluric acid (1-U), 1-methylxanthine (1-X), and a concomitant decrease in the caffeine demethylation product 1,7-dimethylxanthine (1,7-X) was observed after application of BNF. The ratio of the caffeine metabolites (1-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 human CNS-I. In male jj Gunn rats treated with BNF or with indole-3-carbinol (I3C, 80 mg/kg, oral gavage), the inducing effect of BNF and 13C on CYP1A activity was confirmed by the urinary pattern of caffeine metabolites, and was parallelled by a decrease in plasma bilirubin levels. These data demonstrate the usefulness of the established caffeine assay for the evaluation of inducers of CYP1A as tools for reducing hyperbilirubinemia and further confirm the potential value of I3C in the treatment of CNS-I.
Jorritsma
U
U
Department of Toxicology, Institute of Pharmacology and Toxicology, University of Göttingen, Robert-Koch Str. 40, D-37075, Göttingen, Germany.
Schrader
E
E
Klaunick
G
G
Kapitulnik
J
J
Hirsch-Ernst
K I
KI
Kahl
G F
GF
Foth
H
H
D000818:Animals; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers; D002110:Caffeine / Q000652:urine*; D000697:Central Nervous System Stimulants / Q000652:urine*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006932:Hyperbilirubinemia / Q000652:urine*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013045:Species Specificity; D019324:beta-Naphthoflavone / Q000494:pharmacology
D015415:Biomarkers; D000697:Central Nervous System Stimulants; D007211:Indoles; D002110:Caffeine; D019324:beta-Naphthoflavone; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D001663:Bilirubin