Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.
Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.
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发表时间：
1994-07
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通讯作者：
T. Shimada;H. Yamazaki;M. Mimura;Y. Inui;F. Guengerich
中科院分区：
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作者：
T. Shimada;H. Yamazaki;M. Mimura;Y. Inui;F. Guengerich
研究了30例日本人和30例高加索人肝微粒体细胞色素P-450酶水平和活性的个体间差异。本研究所用的P-450酶包括P-450 1A 2、2A 6、2B 6、2C、2D 6、2 E1和3A，测定的单加氧酶活性为13种典型的P-450底物和9种前致癌物。虽然总P-450含量在高加索人（平均值，0.43 nmol/mg蛋白质）高于日本人群（平均值，0.26 nmol/mg蛋白质），相对水平（总P-450的百分比）的P-450的个别形式确定的免疫化学没有很大的差异，除了P-450 2A 6和2B 6水平在高加索人更高。P-450 1A 2、2A 6、2B 6、2C、2D 6、2 E1和3A蛋白约占肝脏P-450的70%，其中3A和2C酶约占总P-450的30%。可测定相当水平的P-450 1A 2（约13%）和2 E1（约7%），而P-450 2A 6（约4%）、2D 6（约2%）和2B 6（< 1%）是次要的P-450形式。在日本和高加索人群中观察到一些P-450 1A 2-、2A 6-、2D 6-、2 E1-和3A 4-依赖性活性的差异。在60个人类样本中，除了P-450 1A 2依赖性活动的平均值高于仅在高加索人群中的女性外，未检测到个体P-450含量和药物及致癌物质代谢活动的明显性别相关差异。单个新生儿样本的P-450 1A 2-、2A 6-和2 E1-依赖性活性往往较低。与大鼠相比，我们无法检测到12至73岁之间人类P-450含量和活性的明显发育变化。因此，本研究结果为药物在人体内的生物转化研究以及药物毒性、致癌和致畸的基础提供了有用的信息。
Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 (about 4%), 2D6 (about 2%) and 2B6 (< 1%) were the minor P-450 forms. Differences in some of the P-450 1A2-, 2A6-, 2D6-, 2E1- and 3A4-dependent activities were observed in Japanese and Caucasian populations. No clear sex-related differences in individual P-450 contents and drug- and carcinogen-metabolizing activities were detected in 60 human samples, except that P-450 1A2-dependent activities were found to be higher in mean than in women in the Caucasian population only. A single neonate sample tended to be lower in P-450 1A2-, 2A6- and 2E1-dependent activities. In contrast to rat counterparts, we could not detect apparent developmental changes in P-450 content and activity in humans between 12 and 73 years old. Thus, the results presented in this study provide useful information for the study of drug biotransformation in humans and for the basis of drug toxicities, carcinogenesis and teratogenesis.