STYRENE METABOLISM BY CDNA-EXPRESSED HUMAN HEPATIC AND PULMONARY CYTOCHROMES P450
STYRENE METABOLISM BY CDNA-EXPRESSED HUMAN HEPATIC AND PULMONARY CYTOCHROMES P450
复制标题
DOI：
10.1021/tx00042a026
复制
发表时间：
1994-11-01
影响因子：
4.1
通讯作者：
AOYAMA, T
中科院分区：
文献类型：
--
作者：
NAKAJIMA, T;ELOVAARA, E;AOYAMA, T
比较了人、大鼠和小鼠肝微粒体中从苯乙烯生成苯乙烯乙二醇的速率。在低浓度(0.085 mM)时，上述速率依次为：小鼠(2.43+/-0.29nmol(mg蛋白·min))和人(0.73+/-0.45)，在高浓度(1.85 mM)时，依次为大鼠(4.21+/-0.72)、小鼠(2.72+/-0.11)和人(1.91+/-0.84)。动力学分析表明，人肝微粒体中至少存在两种形式的苯乙烯代谢细胞色素P450，其K-m值不同。人的肺微粒体内也代谢了苯乙烯：吸烟者的肺微粒体内的苯乙二醇生成率高于现在不吸烟的人。通过分析重组痘苗病毒在培养的肝癌G2细胞中表达的单个P450形式，确定了负责将苯乙烯转化为苯乙二醇的P450形式。在所研究的12种人类P450形式中，存在于人肝和/或肺中的细胞色素P450 B6和细胞色素P450 1和存在于人肺中的细胞色素P450 1对形成苯乙二醇的活性最高，其次是细胞色素P450 1A2和细胞色素P450 C8。人的细胞色素P3A3、细胞色素P3A4、细胞色素P3A5和细胞色素P4B1也能催化代谢，但活性要低得多。细胞色素P450 2 A6、细胞色素P4 2 C9和细胞色素P4 2 D6仅有少量可检测的活性。人肝微粒体表达细胞色素P450 1A2、细胞色素P450 2 B6、细胞色素P450 2 C8、细胞色素P4 2 E1和细胞色素P3 A4/3A3，肺微体表达细胞色素P2 8，但未检测到细胞色素P450 2 F1和细胞色素P4B1的表达。这些数据表明，几个人的肝脏
The rate of formation of styrene glycol from styrene was compared in human, rat, and mouse liver microsomes. At a low styrene concentration (0.085 mM), the rates decreased in the order, mouse (2.43 +/- 0.29 nmol(mg of protein.min)) > rat (1.07 +/- 0.20) > human (0.73 +/- 0.45); at a high concentration (1.85 mM), the order was rat (4.21 +/- 0.72) > mouse (2.72 +/- 0.11) > human (1.91 +/- 0.84). Kinetic analysis indicated the presence of at least two forms of styrene metabolizing cytochrome P450s with different K-m values in human liver microsomes. Styrene was also metabolized in human lung microsomes: the rate of styrene glycol formation was higher in the lung microsomes from smokers than in those from current nonsmokers. The P450 forms responsible for transforming styrene to styrene glycol were determined by analyzing cDNA-expressed individual P450 forms produced in cultured hepatoma G2 cells by recombinant vaccinia viruses. Of the 12 human P450 forms studied, CYP2B6 and CYP2E1 existing in human liver and/or lungs and CYPBF1 in human lungs were the most active in the forming of styrene glycol, followed by CYP1A2 and CYP2C8. Human CYP3A3, CYP3A4, CYP3A5, and CYP4B1 also catalyzed the metabolism but were much less active. CYP2A6, CYP2C9, and CYP2D6 had only a little detectable activity. CYP1A2, CYP2B6, CYP2C8, CYP2E1, and CYP3A4/3A3 were expressed in human liver microsomes, and CYP2C8 was expressed in human lung microsomes, although the expression of CYP2F1 and CYP4B1 could not be investigated. These data indicate that several human hepatic