Pirmohamed M, Kitteringham N R, Breckenridge A M, Park B K
Department of Pharmacology & Therapeutics, University of Liverpool, U.K.
Biochem Pharmacol. 1992 Dec 15;44(12):2307-14. doi: 10.1016/0006-2952(92)90674-8.
Predisposition to idiosyncratic toxicity with carbamazepine is thought to be due to a deficiency of the detoxication enzyme, microsomal epoxide hydrolase, although in some cases, concurrent administration of enzyme inducers might be a contributory risk factor, by altering the critical balance between bioactivation and detoxication. In this study, a mouse model has been used to determine the factors affecting carbamazepine bioactivation, using covalent binding and cytotoxicity as markers of bioactivation in vitro. Microsomes prepared from mice pre-treated with phenobarbitone increased (relative to the control microsomes) the formation of cytotoxic (12.3% vs 3.2%), protein-reactive (3.0% vs 2.0%) and stable (33.8% vs 18.1%) metabolites of carbamazepine. Similarly, pre-treatment with dexamethasone also increased the formation of the cytotoxic (24.8% vs 6.7%), protein-reactive (2.8% vs 1.5%) and stable (38% vs 19.8%) metabolites of carbamazepine, while beta-naphthoflavone pretreatment did not increase the formation of either the toxic or stable metabolites of carbamazepine when compared with its control microsomes. Co-incubation with gestodene (10-250 microM) resulted in a dose-dependent inhibition of both the bioactivation of carbamazepine and the formation of its stable 10,11-epoxide. SDS-PAGE and immunoblotting of the microsomes with anti-CYP3A antibody revealed the presence of a 52 kDa protein band in each preparation of microsomes, but the relative intensities of the bands, as measured by laser densitometry, were highest with the phenobarbitone and dexamethasone microsomes. The microsomal oxidation of cortisol to 6 beta-hydroxycortisol was also enhanced by pretreatment of mice with phenobarbitone (6.5% vs 2.7%) and dexamethasone (8.2% vs 4.3%), but not beta-naphthoflavone (2.2% vs 1.6%), when compared with their respective control microsomes, and was inhibited (range 25-68% inhibition), with all the microsomes by gestodene (50 microM). Taken collectively, the data in this study demonstrate that in the mouse, induction of the CYP3A subfamily significantly increases carbamazepine bioactivation. It is likely that in humans inducers of the orthologous form of this enzyme, most notably anticonvulsants, may increase the bioactivation of carbamazepine.
卡马西平发生特异质毒性的倾向被认为是由于解毒酶微粒体环氧化物水解酶缺乏所致，不过在某些情况下，同时给予酶诱导剂可能也是一个促成风险因素，因为它会改变生物活化与解毒之间的关键平衡。在本研究中，已使用小鼠模型来确定影响卡马西平生物活化的因素，采用共价结合和细胞毒性作为体外生物活化的标志物。用苯巴比妥预处理的小鼠制备的微粒体增加了（相对于对照微粒体）卡马西平细胞毒性代谢物（12.3% 对 3.2%）、蛋白质反应性代谢物（3.0% 对 2.0%）和稳定代谢物（33.8% 对 18.1%）的形成。同样，用地塞米松预处理也增加了卡马西平细胞毒性代谢物（24.8% 对 6.7%）、蛋白质反应性代谢物（2.8% 对 1.5%）和稳定代谢物（38% 对 19.8%）的形成，而与对照微粒体相比，β - 萘黄酮预处理并未增加卡马西平毒性或稳定代谢物的形成。与孕二烯酮（10 - 250 microM）共同孵育导致卡马西平生物活化及其稳定的10,11 - 环氧化物形成呈剂量依赖性抑制。用抗CYP3A抗体对微粒体进行SDS - PAGE和免疫印迹分析显示，每种微粒体制备物中均存在一条52 kDa的蛋白带，但通过激光密度测定法测量，苯巴比妥和地塞米松微粒体的条带相对强度最高。与各自的对照微粒体相比，用苯巴比妥（6.5% 对 2.7%）和地塞米松（8.2% 对 4.3%）预处理小鼠也增强了皮质醇向6β - 羟基皮质醇的微粒体氧化，但β - 萘黄酮预处理则未增强（2.2% 对 1.6%），并且孕二烯酮（50 microM）对所有微粒体的该氧化过程均有抑制作用（抑制范围为25 - 68%）。总体而言，本研究数据表明，在小鼠中，CYP3A亚家族的诱导显著增加了卡马西平的生物活化。在人类中，这种酶的直系同源形式的诱导剂，最显著的是抗惊厥药，可能会增加卡马西平的生物活化。
