Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity
Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity
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DOI：
10.1006/taap.1998.8403
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发表时间：
1998-05-01
影响因子：
3.8
通讯作者：
Bornheim, LM
中科院分区：
文献类型：
--
作者：
Bornheim, LM
检查了几种细胞色素P450（P450）诱导剂对可卡因代谢的影响，以表征导致可卡因诱导的肝毒性的代谢事件。苯巴比妥（PB）预处理小鼠诱导P450 3A和2B，并显着增加血清丙氨酸氨基转移酶（ALT）活性后，可卡因或去甲可卡因管理。虽然地塞米松（Dex）诱导P450的3A和2B至少在相同程度上的PB，没有增加血清ALT活性后，可卡因或去甲可卡因管理观察。苯环利定（PCP）预处理不增加P450的3A或2B，但它显着增强可卡因或去甲可卡因诱导的血清ALT活性。与P450 3A和2B的显著诱导相反，PB仅使P450 2C增加2.5倍，Dex或PCP在更小程度上使P450 3A和2C失活，大麻二酚（CBD）完全保护小鼠免受可卡因或去甲可卡因诱导的肝毒性，无论它们是否用PB或PCP诱导。PB和Dex预处理增加了可卡因（norcocaine和N-hydroxynorcocaine）的前两个连续氧化代谢产物的体外肝微粒体形成，而PCP预处理则没有。在用P450诱导剂预处理后还测定了肝酯酶活性，因为这是可卡因代谢中的主要解毒途径。地塞米松预处理显著增加（>11倍）总肝酯酶活性，而PB预处理增加较少（小于4倍），PCP预处理几乎没有影响。Dex预处理的这种显著作用可能降低肝脏可卡因浓度，从而改善小鼠对可卡因诱导的肝毒性的抵抗，尽管其P450 2B和3A含量增加。(C)北京：科学出版社.
The effect of several cytochrome P450 (P450) inducers on cocaine metabolism were examined in order to characterize the metabolic events contributing to cocaine-induced hepatotoxicity. Phenobarbital (PB)-pretreatment of mice induced P450s 3A and 2B and markedly increased serum alanine aminotransferase (ALT) activity after cocaine or norcocaine administration. Although dexamethasone (Dex) induced P450s 3A and 2B at least to the same extent as PB, no increase in serum ALT activity was observed after cocaine or norcocaine administration. Phencyclidine (PCP) pretreatment did not increase either P450s 3A or 2B, yet it markedly enhanced cocaine- or norcocaine-induced serum ALT activity. In contrast to the marked induction of P450s 3A and 2B, P450 2C was increased only 2.5-fold by PB and to an even lesser extent by Dex or PCP, Cannabidiol (CBD), which inactivates P450s 3A and 2C in mice, completely protected mice against cocaine-or norcocaine-induced hepatotoxicity irrespective of whether they were induced or not with PB or PCP. Both PB and Dex pretreatment increased the in vitro hepatic microsomal formation of the first two sequential oxidative metabolites of cocaine (norcocaine and N-hydroxynorcocaine), whereas PCP pretreatment did not. Hepatic esterase activity was also determined after pretreatment with P450 inducers, since this is the major detoxification pathway in cocaine metabolism. Dex pretreatment markedly increased (>11-fold) total hepatic esterase activity, whereas PB pretreatment increased it more modestly (less than fourfold) and PCP pretreatment had little effect. This marked effect of Dex pretreatment may decrease liver cocaine concentrations and thus prefect mice against cocaine-induced hepatotoxicity, despite their increased P450 2B and 3A contents. (C) 1998 Academic Press.