Studies of the Toxicological Potential of Capsinoids, XIII: Inhibitory Effects of Capsaicin and Capsinoids on Cytochrome P450 3A4 in Human Liver Microsomes

This study evaluated potential effects of a number of capsinoids (ie, capsiate, dihydrocapsiate, nordihydrocapsiate) and a single capsaicinoid (ie, capsaicin) on liver microsomal cytochrome P450 3A4-mediated midazolam I'-hydroxylase activity. Where possible, an inhibition curve was prepared; the concentration at which enzyme activity dropped to 50% was calculated. Capsaicin clearly inhibited cytochrome P450 3A4 activity, losing 50% of the activity at 21.5 mu mol/L. No enzyme inhibition was observed in the presence of capsiate, dihydrocapsiate, or nordihydrocapsiate (<100 mu mol/L). Preincubation increased the capsaicin inhibitory activity against cytochrome P450 3A4 in a time-dependent manner. Enzyme activity was slightly reduced by capsiate, dihydrocapsiate, and nordihydrocapsiate to the same level as that attained with tolbutamide, the negative control compound. Capsaicin was shown to inhibit cytochrome P450 3A4, probably through a mechanism-based inhibition. In contrast, capsiate, dihydrocapsiate, and nordihydrocapsiate did not inhibit cytochrome P450 3A4 activity and were unlikely to be mechanism-based inhibitors of CYP3A4.