Tateishi T, Asoh M, Yamaguchi A, Yoda T, Okano Y J, Koitabashi Y, Kobayashi S
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Pediatr Res. 1999 Jan;45(1):66-70. doi: 10.1203/00006450-199901000-00011.
We investigated the developmental changes in the pattern of urinary metabolites of theophylline, a substrate for CYP1A2, to study when CYP1A2, which is absent in the perinatal period, fully develops during childhood. The urinary ratios of three metabolites (1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid) to theophylline in patients over 3 y of age show a much larger interindividual variation compared with those under 3 y of age, and the mean values of the ratios in patients over 3 y of age were greater than those in patients under 1 y of age. The urinary ratio of 1,3-dimethyluric acid (a metabolite generated by several cytochrome P450s) to 3-methylxanthine or 1-methyluric acid (metabolites generated by CYP1A2 exclusively) seemed to be relatively constant over 3 y of age; in patients under 3 y of age, these ratios were much higher than those in patients over 3 y of age. The urinary ratio of 1-methyluric acid to 3-methylxanthine or 3-methylxanthine to 1-methyluric acid seemed to be relatively invariable in all patients except those less than 1 y of age. These findings suggest that CYP1A2 activity may be programmed to mature by around 3 y of age and that CYP1A2 probably plays a major role in theophylline 8-hydroxylation at a therapeutic concentration after the full development of CYP1A2 activity.
我们研究了细胞色素P450 1A2（CYP1A2）底物茶碱的尿代谢产物模式的发育变化，以研究围生期不存在的CYP1A2在儿童期何时完全发育。与3岁以下患者相比，3岁以上患者中三种代谢产物（1-甲基尿酸、3-甲基黄嘌呤和1,3-二甲基尿酸）与茶碱的尿比率显示出更大的个体间差异，且3岁以上患者的比率平均值高于1岁以下患者。1,3-二甲基尿酸（由几种细胞色素P450产生的代谢产物）与3-甲基黄嘌呤或1-甲基尿酸（仅由CYP1A2产生的代谢产物）的尿比率在3岁以上似乎相对恒定；在3岁以下患者中，这些比率远高于3岁以上患者。1-甲基尿酸与3-甲基黄嘌呤的尿比率或3-甲基黄嘌呤与1-甲基尿酸的尿比率在除1岁以下患者外的所有患者中似乎相对不变。这些发现表明，CYP1A2活性可能在3岁左右编程成熟，并且在CYP1A2活性完全发育后，CYP1A2可能在治疗浓度下的茶碱8-羟化中起主要作用。
