Human hepatic CYP2B6 developmental expression: The impact of age and genotype
Human hepatic CYP2B6 developmental expression: The impact of age and genotype
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DOI：
10.1016/j.bcp.2009.03.029
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发表时间：
2009-07-15
影响因子：
5.8
通讯作者：
Hodgson, Ernest
中科院分区：
文献类型：
--
作者：
Croom, Edward L.;Stevens, Jeffrey C.;Hodgson, Ernest
虽然已知CYP 2B 6在成人中代谢许多药物和毒物，但关于CYP 2B 6个体发育或其在儿科药物/毒物代谢中的可能作用知之甚少。为了解决这一知识缺口，在从儿科肝脏库（N = 217）分离的微粒体蛋白制备物中表征了肝脏CYP 2B 6蛋白水平。供体年龄范围从妊娠10周至17岁，中位年龄为1.9个月。通过半定量蛋白质印迹法测定CYP 2B 6水平。总体而言，在75%的样本中检测到CYP 2B 6表达。然而，可检测到CYP 2B 6蛋白的样本百分比随着年龄的增长而增加，从胎儿样本的64%增加到10岁以上供体样本的95%。有一个显着的，但只有2倍的增加，中位CYP 2B 6的表达后，新生儿期（出生后30天），虽然蛋白质水平变化超过25倍，在两个年龄组。出生后30天至17岁的样本中的中位CYP 2B 6水平（1.3 pmol/mg微粒体蛋白）低于先前报告的成人水平（2.2-22 pmol/mg微粒体蛋白），然而，这可能与这些样本的中位年龄有关，即，10.3个月CYP 2B 6表达在性别间无显著差异。此外，CYP 2B 6水平与CYP 3A 4、CYP3A5.1或CYP 3A 7活性不相关，这与控制这些酶的个体发育和组成型表达的不同机制以及儿科样本中缺乏显著诱导一致。(C)2009 Elsevier Inc. All rights reserved.
Although CYP2B6 is known to metabolize numerous pharmaceuticals and toxicants in adults, little is known regarding CYP2B6 ontogeny or its possible role in pediatric drug/toxicant metabolism. To address this knowledge gap, hepatic CYP2B6 protein levels were characterized in microsomal protein preparations isolated from a pediatric liver bank (N = 217). Donor ages ranged from 10 weeks gestation to 17 years of age with a median age of 1.9 months. CYP2B6 levels were measured by semi-quantitative western blotting. Overall, CYP2B6 expression was detected in 75% of samples. However, the percentage of samples with detectable CYP2B6 protein increased with age from 64% in fetal samples to 95% in samples from donors > 10 years of age. There was a significant, but only 2-fold increase in median CYP2B6 expression after the neonatal period (birth to 30 days postnatal) although protein levels varied over 25-fold in both age groups. The median CYP2B6 level in samples over 30 postnatal days to 17 years of age (1.3 pmol/mg microsomal protein) was lower than previously reported adult levels (2.2-22 pmol/mg microsomal protein), however, this likely relates to the median age of these samples, i.e., 10.3 months. CYP2B6 expression did not vary significantly by gender. Furthermore, CYP2B6 levels did not correlate with CYP3A4, CYP3A5.1 or CYP3A7 activity, consistent with different mechanisms controlling the ontogeny and constitutive expression of these enzymes and the lack of significant induction in the pediatric samples. (C) 2009 Elsevier Inc. All rights reserved.