Developmental expression of human hepatic CYP2C9 and CYP2C19
Developmental expression of human hepatic CYP2C9 and CYP2C19
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DOI：
10.1124/jpet.103.060137
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发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Hines, RN
中科院分区：
文献类型：
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作者：
Koukouritaki, SB;Manro, JR;Hines, RN
CYP 2C亚家族负责许多重要药物的代谢，约占成人肝脏细胞色素P450的20%。为了确定发育表达模式，通过蛋白质印迹法分别以双氯芬酸或美芬妥英作为探针底物测定了肝微粒体CYP 2C 9和-2C19（n = 237;年龄，妊娠8周至18岁）。CYP 2C 9特异性含量和催化活性与成熟值的1 - 2%表达一致（即，比含量，18.3 pmol/mg蛋白质和n = 79;比活性，549.5 pmol/mg/min和n = 72），在妊娠中期和妊娠晚期逐渐增加至成熟值的约30%。从出生到5个月，CYP 2C 9蛋白值变化35倍，显著高于胎儿晚期观察到的值，51%的样本显示与成熟水平相当的值。在5个月至18岁之间观察到的CYP 2C 9蛋白和活性值变化较小。CYP 2C 19蛋白和催化活性为成熟值的12 - 15%（即，比含量，14.6 pmol/mg，n = 20;比活性，18.5 pmol/mg/min，n = 19），早在妊娠8周就观察到，并且在整个产前期间相似。CYP 2C 19表达在出生时没有变化，在出生后的前5个月内线性增加，从5个月到10岁变化21倍。在10岁以上的样本中观察到成人CYP 2C 19蛋白和活性值。CYP 2C 9和-2C19的个体发生在胎儿和出生后0- 5个月的样本中是不同的，这意味着不同的发育调节机制。
The CYP2C subfamily is responsible for metabolizing many important drugs and accounts for about 20% of the cytochrome P450 in adult liver. To determine developmental expression patterns, liver microsomal CYP2C9 and -2C19 were measured (n = 237; ages, 8 weeks gestation-18 years) by Western blotting and with diclofenac or mephenytoin, respectively, as probe substrates. CYP2C9-specific content and catalytic activity were consistent with expression at 1 to 2% of mature values (i.e., specific content, 18.3 pmol/mg protein and n = 79; specific activity, 549.5 pmol/mg/min and n = 72) during the first trimester, with progressive increases during the second and third trimesters to levels approximately 30% of mature values. From birth to 5 months, CYP2C9 protein values varied 35-fold and were significantly higher than those observed during the late fetal period, with 51% of samples exhibiting values commensurate with mature levels. Less variable CYP2C9 protein and activity values were observed between 5 months and 18 years. CYP2C19 protein and catalytic activities that were 12 to 15% of mature values (i.e., specific content, 14.6 pmol/mg and n = 20; specific activity, 18.5 pmol/mg/min and n = 19) were observed as early as 8 weeks of gestation and were similar throughout the prenatal period. CYP2C19 expression did not change at birth, increased linearly over the first 5 postnatal months, and varied 21-fold from 5 months to 10 years. Adult CYP2C19 protein and activity values were observed in samples older than 10 years. The ontogeny of CYP2C9 and -2C19 were dissimilar among both fetal and 0- to 5-months postnatal samples, implying different developmental regulatory mechanisms.