Bornheim L M, Everhart E T, Li J, Correia M A
Department of Pharmacology, University of California, San Francisco 94143-0450.
Biochem Pharmacol. 1994 Jul 5;48(1):161-71. doi: 10.1016/0006-2952(94)90236-4.
Cannabidiol (CBD) has been shown to be a selective inactivator of cytochromes P450 (P450s) 2C and 3A in the mouse and, like many P450 inactivators, it can also induce P450s after repeated administration. The inductive effects of CBD on mouse hepatic P450s 2B, 3A, and 2C were determined using cDNA probes, polyclonal antibodies, and specific functional markers. P450 2B10 mRNA was increased markedly after repeated CBD administration and correlated well with increased P450 2B immunoquantified content and functional activity. On the other hand, although the 2-fold increase in P450 3A mRNA detected after repeated CBD administration was consistent with the increased immunoquantified P450 3A protein content, the lack of an observable increase in P450 3A-specific functional activity suggested subsequent inactivation of the induced P450 3A. Repeated CBD treatment increased P450 2C mRNA content 2-fold, but did not increase either the P450 2C immunoquantified content or its functional activity. The effect of CBD treatment on the ability of tetrahydrocannabinol (THC) to induce P450 2B was also determined. A THC dose that did not induce P450 2B significantly was administered alone or in combination with a CBD dose that markedly inactivated P450s 2C- and 3A but submaximally increased P450 2B functional activity. The combination of THC and CBD did not increase P450 2B-catalyzed activity significantly over that observed after CBD treatment alone. Thus, prior CBD-mediated P450 inactivation does not appear to increase the ability of THC to induce P450 2B. To further characterize the relationship between P450 inactivation and induction, several structurally diverse CBD analogs with varying P450 inactivating potentials were tested for their ability to induce P450 2B. At least one CBD analog that is an effective P450 inactivator failed to induce P450 2B, while at least one CBD analog that is incapable of inactivating P450 was found to be a very good P450 2B inducer. It therefore appears that inherent structural features of the CBD molecule rather than its ability to inactivate P450 determine P450 2B inducibility. The complex effects of CBD treatment on P450 inactivation and induction have the potential to influence the pharmacological action of many clinically important drugs known to be metabolized by these various P450s. The mechanism of CBD-mediated P450 induction remains to be elucidated but does not appear to be related to CBD-mediated P450 inactivation.
大麻二酚（CBD）已被证明是小鼠细胞色素P450（P450s）2C和3A的选择性失活剂，并且与许多P450失活剂一样，反复给药后它也能诱导P450s。使用cDNA探针、多克隆抗体和特定功能标记物测定了CBD对小鼠肝脏P450s 2B、3A和2C的诱导作用。反复给予CBD后，P450 2B10 mRNA显著增加，并且与P450 2B免疫定量含量和功能活性的增加密切相关。另一方面，尽管反复给予CBD后检测到P450 3A mRNA增加了2倍，这与免疫定量的P450 3A蛋白含量增加一致，但P450 3A特异性功能活性没有明显增加，这表明诱导产生的P450 3A随后被失活。反复给予CBD治疗使P450 2C mRNA含量增加了2倍，但未增加P450 2C免疫定量含量或其功能活性。还测定了CBD治疗对四氢大麻酚（THC）诱导P450 2B能力的影响。单独给予或与显著使P450s 2C和3A失活但使P450 2B功能活性亚最大程度增加的CBD剂量联合给予未显著诱导P450 2B的THC剂量。THC和CBD的组合并未比单独给予CBD治疗后观察到的P450 2B催化活性显著增加。因此，先前CBD介导的P450失活似乎并未增加THC诱导P450 2B的能力。为了进一步表征P450失活与诱导之间的关系，测试了几种具有不同P450失活潜力的结构多样的CBD类似物诱导P450 2B的能力。至少一种作为有效P450失活剂的CBD类似物未能诱导P450 2B，而至少一种不能使P450失活的CBD类似物被发现是一种非常好的P450 2B诱导剂。因此，似乎是CBD分子的固有结构特征而非其使P450失活的能力决定了P450 2B的诱导性。CBD治疗对P450失活和诱导的复杂影响有可能影响许多已知由这些不同P450代谢的临床重要药物的药理作用。CBD介导的P450诱导机制仍有待阐明，但似乎与CBD介导的P450失活无关。
