Administration of the imidazole antifungal agents ketoconazole, miconazole and clotrimazole gave rise to increases in the microsomal cytochrome P-450 levels and the NADPH-dependent reduction of cytochrome c. Clotrimazole, and to a much lesser extent miconazole and ketoconazole, stimulated the dealkylation of pentoxyresorufin. All 3 agents gave rise to small, but significant increases in the O-deethylations of ethoxycoumarin and ethoxyresorufin. The antifungal-induced O-deethylation of ethoxycoumarin was much more sensitive to inhibition by metyrapone rather than by -naphthoflavone. The binding of metyrapone to reduced microsomes was enhanced by treatment of animals with the 3 antifungal agents, clotrimazole being clearly the most potent. Immunoquantitation of cytochrome P-450 proteins using an ELISA procedure and employing anti-cytochrome P-450c (P-450IA1, P-448 low spin) and P-450b (P-450IIB1) antisera revealed that clotrimazole and miconazole, but not ketoconazole, induced the levels of phenobarbital-induced cytochromes P-450, while none of the antifungal agents increased the levels of cytochrome of P-448 proteins. Similar results were obtained using Western blots employing the above antibodies.
On SDS-polyacrylamide gel electrophoresis microsomes derived from animals pretreated with clotrimazole showed intensification of a band at 51 kDa which was identified by Western blotting as the PCN-inducible form of cytochrome P-450 (cytochrome P-450p, P-450III family). Similar, but less pronounced intensification was seen with microsomes from animals pretreated with miconazole and ketoconazole. Furthermore, microsomes from clotrimazole- and ketoconazole-treated animals interacted with erythromycin to yield type I spectra.
It is concluded that the imidazole-containing agents clotrimazole and miconazole, and to a much lesser extent ketoconazole, are potent inducers of the rat hepatic microsomal mixed-function oxidases, displaying selectivity towards the P-450IIB (phenobarbital-inducible) and P-450III (PCN-inducible) families of cytochrome P-450 proteins. 相似文献
It is now well established that the imidazoline insulin secretagogue efaroxan mediates its effects by inducing closure of
ATP-sensitive potassium channels in the pancreatic β-cell, leading to membrane depolarisation, Ca2+ influx and increased insulin secretion. However, a recent study has shown that efaroxan may also act as a blocker of a second
class of potassium channel (the Kmaxi channel) in red blood cells, raising the possibility that its effects in islets could be mediated by interactions with both
types of channel. Since the antimycotic imidazole compound clotrimazole is a highly potent blocker of Kmaxi channels, we have studied the effects of this drug on insulin secretion.
Received: 10 July 1997 / Accepted: 2 September 1997 相似文献
Cell adhesion molecules play a pivotal role in chronic inflammation and pathological angiogenesis. In the present study, we
investigated the inhibitory effects of clotrimazole (CLT) on tumor necrosis factor (TNF)-α-induced changes in adhesion molecule
expression. CLT dose-dependently inhibited monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1
(ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expressions in TNF-α-stimulated HT29 colonic epithelial cells. This
inhibitory action of CLT correlated with a significant reduction in TNF-α-induced adhesion of monocytes to HT29 cells, which
was comparable to the inhibitory effects of anti-ICAM-1 and VCAM-1 monoclonal antibodies on monocyte-epithelial adhesion.
These inhibitory actions of CLT were, at least in part, attributable to the inhibition of redox sensitive NF-κB activation,
as CLT inhibited TNF-α-induced ROS generation as well as NF-κB nuclear translocation and activation in HT29 cells. Furthermore,
the inhibition of TNF-α-induced monocyte adhesion was also mimicked by the specific NF-κB inhibitor, pyrrolidine dithiocarbamate
(PDTC). Inflammatory mediators including TNF-α have known to promote angiogenesis, which in turn further contributes to inflammatory
pathology. Therefore, we additionally evaluated whether CLT modulates TNF-α-induced angiogenesis using in vivo chick chorioallantoic membrane (CAM) assay. The CAM assay showed that CLT dose-dependently attenuated TNF-α-induced angiogenesis,
and the effect was correlated with decreased inflammation of the CAM tissue. In conclusion, our results suggest that CLT can
inhibit TNF-α-triggered expression of adhesion molecules, ICAM-1 and VCAM-1, and angiogenesis during inflammation. 相似文献