Caffeine metabolism in cystic fibrosis: enhanced xanthine oxidase activity.
OBJECTIVE
To characterize the activities of the P450 mixed-function oxidase CYP1A2 as well as the cytosolic enzymes N-acetyltransferase and xanthine oxidase using caffeine as a probe in children with cystic fibrosis compared to age-matched healthy control subjects.


METHODS
After administration of caffeine (cola beverage) to 12 children with cystic fibrosis (age range, 5 to 11 years) and 12 healthy control subjects (age range, 5 to 12 years), urine was collected for 4 hours. Caffeine metabolites were determined by HPLC, and urinary caffeine metabolite ratios were computed to determine liver enzyme activities. In addition, a blood sample was used to detect cystic fibrosis mutant alleles by polymerase chain reaction.


RESULTS
The indexes for CYP1A2, N-acetyltransferase, and 8-hydroxylation were similar in both groups of subjects. In contrast, there was a significant difference in the frequency distribution of the xanthine oxidase activity between the two groups. Nine of 12 patients with cystic fibrosis but only one of 12 healthy volunteers had xanthine oxidase activities above 0.42 (Kolmogorov-Smirnov two-sample test, p < 0.01).


CONCLUSIONS
Differences in xanthine oxidase may have clinical implications with regard to interindividual variation in xenobiotic biotransformation and the exposure to lung tissue-damaging oxygen radicals. Hepatic enzyme activities appear to be selectively altered in patients with cystic fibrosis.
Ecole de Pharmacie, Laboratoire de Pharmacocinétique Clinique, Cité Universitaire, Université Laval, Québec, Canada.
B A
BA
Hamelin
K
K
Xu
F
F
Vallé
L
L
Manseau
M
M
Richer
M
M
LeBel
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D001483:Base Sequence; D002110:Caffeine / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014969:Xanthine Oxidase / Q000378:metabolism*
D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D014969:Xanthine Oxidase; D001191:Arylamine N-Acetyltransferase