HUMAN LIVER CARBAMAZEPINE METABOLISM - ROLE OF CYP3A4 AND CYP2C8 IN 10,11-EPOXIDE FORMATION
HUMAN LIVER CARBAMAZEPINE METABOLISM - ROLE OF CYP3A4 AND CYP2C8 IN 10,11-EPOXIDE FORMATION
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DOI：
10.1016/0006-2952(94)90071-x
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发表时间：
1994-06-01
影响因子：
5.8
通讯作者：
LEVY, RH
中科院分区：
文献类型：
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作者：
KERR, BM;THUMMEL, KE;LEVY, RH
许多药物抑制细胞色素P450催化的卡马西平代谢，有时导致卡马西平中毒。然而，有关负责该药物代谢的P450特定亚型的身份的信息很少。本研究探讨了CYP 3A 4在卡马西平主要代谢产物卡马西平-10，11-环氧化物形成中的作用。研究结果表明：（1）纯化的CYP 3A 4催化10，11-环氧化;（2）cDNA表达的CYP 3A 4催化10，11-环氧化（V-max = 1730 pmol/min/nmol P450，K-m = 442 μ M）;（3）16份人肝微粒体中10，11-环氧化速率与CYP 3A 4含量呈显著正相关（r（2）= 0.57，P < 0.001）;（4）三乙酰竹桃霉素和抗CYP 3A 4 IgG将10，11-环氧化减少至31 +/- 6%（16个肝脏）和43 +/- 2%（四肝）的控制率;和（5）微粒体10，11-环氧化而不是苯酚的形成被α-萘甲酮和孕酮以及卡马西平本身激活2- 3倍（底物激活）。这些发现表明，CYP 3A 4是人肝脏中10，11-环氧化物形成的主要催化剂。利用一组P450亚型选择性抑制剂的实验也表明CYP 2C 8在肝微粒体10，11-环氧化中有轻微参与。在卡马西平与cDNA表达的CYP 2C 8孵育中证实了CYP 2C 8的环氧化作用。CYP 3A 4在卡马西平消除的主要途径中的作用与其临床使用相关的抑制性药物相互作用的数量一致，这些相互作用是由CYP 3A 4催化活性扰动引起的。
A number of drugs inhibit the metabolism of carbamazepine catalyzed by cytochrome P450, sometimes resulting in carbamazepine intoxication. However, there is little information available concerning the identity of the specific isoforms of P450 responsible for the metabolism of this drug. This study addressed the role of CYP3A4 in the formation of carbamazepine-10,11-epoxide, the major metabolite of carbamazepine. Results of the study showed that: (1) purified CYP3A4 catalyzed 10,11-epoxidation; (2) cDNA-expressed CYP3A4 catalyzed 10,11-epoxidation (V-max = 1730 pmol/min/nmol P450, K-m = 442 mu M); (3) the rate of 10,11-epoxidation correlated with CYP3A4 content in microsomes from sixteen human livers (r(2) = 0.57, P < 0.001); (4) triacetyloleandomycin and anti-CYP3A4 IgG reduced 10,11-epoxidation to 31 +/- 6% (sixteen livers) and 43 +/- 2% (four livers) of control rates, respectively; and (5) microsomal 10,11-epoxidation but not phenol formation was activated 2- to 3-fold by alpha-naphthoflavone and progesterone and by carbamazepine itself (substrate activation). These findings indicate that CYP3A4 is the principal catalyst of 10,11-epoxide formation in human liver. Experiments utilizing a panel of P450 isoform selective inhibitors also suggested a minor involvement of CYP2C8 in liver microsomal 10,11-epoxidation. Epoxidation by CYP2C8 was confirmed in incubations of carbamazepine with cDNA-expressed CYP2C8. The role of CYP3A4 in the major pathway of carbamazepine elimination is consistent with the number of inhibitory drug interactions associated with its clinical use, interactions that result from a perturbation of CYP3A4 catalytic activity.