Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.
1. Caffeine metabolism was studied in human liver microsomes from foetuses (n = 10), neonates (n = 10), infants (n = 9) and adults (n = 5). Caffeine and its metabolites, 1-3-7-trimethyluric acid, paraxanthine, theophylline and theobromine, were assayed by h.p.l.c. Methoxyresorufin-O-demethylase activity (MEROD) was determined and immunoquantifiable levels of CYP1A2 were measured. 2. The formation of the dimethylxanthines by N-3, N-7 or N-1-demethylation was significantly less in foetuses, neonates and infants than in adults, as shown previously in vivo. The formation of 1-3-7-trimethyluric acid (C-8-hydroxylation) was not significantly different between age groups. The production of total dimethylxanthines, paraxanthine and theophylline increased significantly with age within the neonate-infant group over at least the 0-300 day range (rs = 0.739, 0.667, 0.682, respectively). These data differ from those reported in vivo which suggested that N-3 and N-7-demethylations matured at about 120 days. The difference in maturational profiles of each metabolic pathway suggests that the reactions depend on different isoenzymes. The delay in the maturation of N-1 compared with N-3 and N-7-demethylation is in agreement with previous in vivo data. 3. In the neonate-infant group, only N-3-demethylation correlated with both MEROD activity (rs = 0.681; P < 0.05) and CYP1A2 microsomal concentration (rs = 0.454; P approximately 0.05), suggesting that, as in adults, this reaction depends on CYP1A2. 4. In the foetal samples, the production of total dimethylxanthines, paraxanthine and theobromine decreased significantly (rs = -0.879, -0.767, -0.708, respectively) with increasing gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)
Cazeneuve
C
C
Département de Pharmacologie Périnatale et Pédiatrique, Hôpital Saint Vincent de Paul, Paris, France.
Pons
G
G
Rey
E
E
Treluyer
J M
JM
Cresteil
T
T
Thiroux
G
G
D'Athis
P
P
Olive
G
G
D000328:Adult; D000375:Aging / Q000378:metabolism*; D001711:Biotransformation; D002110:Caffeine / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism
D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019388:Cytochrome P-450 CYP1A2