Bornheim L M
Department of Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0450, USA.
Toxicol Appl Pharmacol. 1998 May;150(1):158-65. doi: 10.1006/taap.1998.8403.
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 protect mice against cocaine-induced hepatotoxicity, despite their increased P450 2B and 3A contents.
为了确定导致可卡因诱导肝毒性的代谢事件特征，研究了几种细胞色素P450（P450）诱导剂对可卡因代谢的影响。对小鼠进行苯巴比妥（PB）预处理可诱导P450 3A和2B，并在给予可卡因或去甲可卡因后显著增加血清丙氨酸氨基转移酶（ALT）活性。尽管地塞米松（Dex）诱导P450 3A和2B的程度至少与PB相同，但在给予可卡因或去甲可卡因后未观察到血清ALT活性增加。苯环己哌啶（PCP）预处理既未增加P450 3A也未增加P450 2B，但它显著增强了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，P450 2C仅被PB增加了2.5倍，被Dex或PCP增加的程度更小。大麻二酚（CBD）可使小鼠体内的P450 3A和2C失活，无论小鼠是否用PB或PCP诱导，均可完全保护小鼠免受可卡因或去甲可卡因诱导的肝毒性。PB和Dex预处理均增加了可卡因前两个连续氧化代谢产物（去甲可卡因和N-羟基去甲可卡因）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。Dex预处理显著增加（>11倍）了总肝酯酶活性；而PB预处理使其增加幅度较小（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会降低肝脏中的可卡因浓度，从而保护小鼠免受可卡因诱导的肝毒性，尽管它们的P450 2B和P450 3A含量有所增加。
