Ontogeny of human hepatic cytochromes P450
Ontogeny of human hepatic cytochromes P450
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DOI：
10.1002/jbt.20179
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Hines, Ronald N.
中科院分区：
文献类型：
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作者：
Hines, Ronald N.
药物代谢酶（DME）表达的显着变化发生在个体发育。这些变化可能对胎儿和儿童的治疗效果以及药物不良反应的风险产生深远的影响。为了更好地了解DME的个体发生，在240人肝脏样本中测量了6个关键细胞色素P450的酶含量，这些样本的年龄从妊娠8周到18岁。在可能的情况下，使用探针底物进行定量蛋白质印迹和活性测定。虽然过于简单，DME可以分为三类之一。以CYP 3A 7为代表，一些酶在妊娠早期以最高水平表达，并在妊娠期间保持高浓度或降低，并在出生后1-2年内沉默或以低水平表达。这些数据使人怀疑这些酶是否具有重要的内源性功能。第二组的代表，CYP 3A 5和CYP 2C 19，在整个妊娠期间以相对恒定的水平表达。出生后第一年内观察到CYP 2C 19增加，但CYP 3A 5未增加。CYP 2C 9、2 E1和3A 4是更典型的第三组酶，在胎儿中不表达或以低水平表达，通常在妊娠中期或妊娠晚期开始表达。在出生后的前1-2年内观察到表达的显著增加;然而，在出生后立即（1-6个月）开始或这些酶的表达增加时观察到相当大的个体间差异，通常导致高变窗口。
Significant changes in drug-metabolizing enzyme (DME) expression occur during ontogeny. Such changes can have a profound effect on therapeutic efficacy in the fetus and child, as well as the risk for adverse drug reactions. To gain a better understanding of DME ontogeny, enzyme contents for six key cytochromes P450 were measured in 240 human liver samples representing ages from 8 weeks gestation to 18 years. Where possible, both quantitative western blotting and activity assays with probe substrates were performed. Although oversimplified, the DME can be grouped into one of three categories. As typified by CYP3A7, some enzymes are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation and are silenced or expressed at low levels within 1-2 years afterbirth. These data cause one to query whether these enzymes have an important endogenous function. Representatives of a second group, CYP3A5 and CYP2C19, are expressed at relatively constant levels throughout gestation. Postnatal increases in CYP2C19 are observed within the first year, but not for CYP3A5. CYP2C9, 2E1, and 3A4 are more typical of a third group of enzymes that are not expressed or are expressed at low levels in the fetus with the onset of expression generally in either the second or third trimester. Substantial increases in expression are observed within the first 1-2 years after birth; however, considerable interindividual variability is observed in the immediate postnatal (1-6 months) onset or increase in expression of these enzymes, often resulting in a window of hypervariability.