Human hepatic CYP2E1 expression during development
Human hepatic CYP2E1 expression during development
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DOI：
10.1124/jpet.102.053124
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
McCarver, DG
中科院分区：
文献类型：
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作者：
Johnsrud, EK;Koukouritaki, SB;McCarver, DG
人肝脏CYP 2 E1表达的发育变化可能对编码酶代谢的外源性物质的作用产生影响。为了解决之前的矛盾结果，测定了来自胎龄（n = 73，8 - 37周）和出生后（n = 165，1天-18岁）样本的人肝微粒体中的CYP 2 E1含量。在49例中期妊娠（妊娠93 - 186天）胎儿样本中的18例和15例晚期妊娠（> 186天）胎儿样本中的12例中观察到可测量的免疫检测CYP 2 E1（中位数分别为0.35和6.7 pmol/mg微粒体蛋白）。新生儿样本中的CYP 2 E1较低，低于31 - 90日龄婴儿，低于大龄婴儿、儿童和年轻成人[中位数（范围）= 8.8（0 - 70）; 23.8（10 - 43）; 41.4（18 - 95）pmol/mg微粒体蛋白;各P < 0.001，方差分析，事后分析]。在年龄大于90天的人群中，CYP 2 E1含量相似。在每个年龄组的样本中观察到4倍或更大的受试者间变异，新生儿样本中的变异最大，为80倍。在已知胎龄和出生后年龄的受试者中（n = 29），蛋白质含量的增加与出生后年龄的增加相关（P < 0.001，线性回归），但与胎龄的增加无关（P = 0.07）。从妊娠晚期到出生后90天，具有一个或多个CYP 2 E1 *1D等位基因的个体的CYP 2 E1蛋白含量低于年龄相似的纯合子CYP 2 E1 *1C受试者。总之，CYP 2 E1在人胎肝中明确表达。此外，出生后数据表明，与年龄较大的婴儿、儿童和成人相比，小于90天的婴儿的CYP 2 E1底物清除率降低。
Human hepatic CYP2E1 expression developmental changes likely have an impact on the effects of xenobiotics metabolized by the encoded enzyme. To resolve previous conflicting results, CYP2E1 content was determined in human hepatic microsomes from samples spanning fetal (n = 73, 8 - 37 weeks) and postnatal (n = 165, 1 day - 18 years) ages. Measurable immunodetectable CYP2E1 was seen in 18 of 49 second-trimester ( 93 - 186 gestational days) and 12 of 15 third-trimester ( > 186 days) fetal samples ( medians = 0.35 and 6.7 pmol/mg microsomal protein, respectively). CYP2E1 in neonatal samples was low and less than that of infants 31 to 90 days of age, which was less than that of older infants, children, and young adults [ median ( range) = 8.8 ( 0 - 70); 23.8 ( 10 - 43); 41.4 ( 18 - 95) pmol/mg microsomal protein, respectively; each P < 0.001, analysis of variance, post hoc]. Among those older than 90 days of age, CYP2E1 content was similar. A 4-fold or greater intersubject variation was observed among samples from each age group, with the greatest variation, 80-fold, seen among neonatal samples. Among subjects of known gestational and postnatal age ( n = 29) increasing protein content was associated with increasing postnatal age ( P < 0.001, linear regression), but only equivocally with increasing gestational age ( P = 0.07). Individuals from the third trimester through 90 days postnatal age with one or more CYP2E1*1D alleles had lower CYP2E1 protein content than similar-aged subjects who were homozygous CYP2E1*1C. In summary, CYP2E1 was clearly expressed in human fetal liver. Furthermore, the postnatal data suggest that infants less than 90 days old would have decreased clearance of CYP2E1 substrates compared with older infants, children, and adults.