CYP2J11 Inhibitors

Chemical inhibitors of CYP2J11 act through various mechanisms to impede the enzyme's function. Terfenadine and miconazole exert their effects by targeting the potassium channels and the enzyme's heme iron, respectively. Terfenadine is known to block hERG potassium channels, which are modulated by the products of CYP2J11, leading to a reduction in the enzyme's activity. Miconazole, on the other hand, binds directly to the active site of CYP2J11, the heme group, thwarting the normal metabolization process. Ketoconazole employs a similar approach by coordinating to the heme group within CYP2J11, disrupting the enzyme's activity. Montelukast operates indirectly; it lowers the levels of leukotrienes, thereby decreasing substrate availability for CYP2J11 and consequently decreasing the enzyme's activity.

Other inhibitors, such as danazol, clotrimazole, and ticlopidine, interfere with CYP2J11 by various means. Danazol competes with natural substrates for the binding site on CYP2J11, reducing the enzyme's ability to metabolize its actual substrates. Clotrimazole impedes the enzyme's function by binding to its heme iron, which is essential for metabolic activity. Ticlopidine has a unique mechanism where it forms a reactive metabolite that irreversibly binds to CYP2J11, leading to a sustained inhibition. Diethyldithiocarbamate, chloramphenicol, sulfinpyrazone, phenylbutazone, and propylthiouracil each inhibit CYP2J11 through their interactions with the enzyme's active site or the heme group. Diethyldithiocarbamate acts as a chelating agent, binding to the heme iron and interfering with heme-iron catalyzed reactions essential to the enzyme's function. Chloramphenicol binds to the active site, obstructing the catalytic activity. Sulfinpyrazone and phenylbutazone both inhibit through competitive inhibition, directly competing with CYP2J11's substrates. Lastly, propylthiouracil inhibits the enzyme's oxidizing ability, affecting the metabolism of substrates by CYP2J11.