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Background: Hypericin is the main active ingredient of St. John’s wort, a Chinese herb commonly used in treating depression. Previous studies have shown that hypericin can strongly inhibit human cytochrome P450 (CYP) enzyme activities; however, its potential interactions that inhibit human carboxylesterases 2 (hCE2) were unclear. Purpose: The study aimed to investigate the inhibition of hypericin on hCE2. Methods: The inhibition of hypericin on hCE2 was studied by using N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN). The type of inhibition of hypericin on hCE2 and the corresponding inhibition constant (Ki) value were determined. The inhibition of hypericin on hCE2 in living cells was discussed. The herb-drug interactions (HDI) risk of hypericin and hCE2 in vivo was predicted by estimating the drug concentration-time curve (AUC) ratio of hypericin and hypericin free. To understand the inhibition mechanism of hypericin on the activity of hCE2 in-depth, molecular docking was performed. Results: The half-maximal inhibitory concentration (IC50) values of hypericin against the hydrolysis of NCEN and irinotecan (CPT-11) were calculated to be 26.59 μM and 112.8 μM, respectively. Hypericin inhibited the hydrolysis of NCEN and CPT-11. Their Ki values were 10.53 μM and 81.77 μM, respectively. Moreover, hypericin distinctly suppressed hCE2 activity in living cells. In addition, the AUC of hCE2 metabolic drugs with metabolic sites similar to NCEN was estimated to increase by up to 5%, in the presence of hypericin. More importantly, the exposure of CPT-11 in the intestinal epithelium was predicted to increase by 2%–69% following the oral co-administration of hypericin. Further, molecular simulations indicated that hypericin could strongly interact with ASP98, PHE307, and ARG355 to form four hydrogen bonds within hCE2. Conclusion: These findings are of considerable clinical significance to the combination of hypericin-containing herbs and drugs metabolized by hCE2.

CYP46A1 is a brain-specific enzyme responsible for cholesterol homeostasis. Inhibition of CYP46A1 activity serves as a therapeutic target for excitatory neurotoxicity. Sesame is a common medicine and food resource; its component lignans possess various pharmacological activities. In this study, the inhibitory effects of sesame lignans on CYP46A1 activity were investigated. Inhibition kinetics analyses revealed that sesamin and sesamolin produce mixed partial competitive inhibition of CYP46A1, while sesamol produces non-competitive inhibition. Notably, molecular simulations revealed that the sesame lignans have excellent orientations within the active cavity of CYP46A1. Importantly, the sesame lignans had high permeability coefficients and low efflux ratios. Furthermore, sesamin significantly reduced the levels of 24S-hydroxycholesterol in rat plasma and brain tissues, and down-regulated the protein expressions of CYP46A1, NMDAR2A, NMDAR2B, and HMGCR. Collectively, sesame lignans exhibit significant inhibitory effects on CYP46A1 activity, highlighting their potential therapeutic role in treating excitatory neurotoxicity.

This study aimed to investigate the potential nephrotoxicity of icaritin and the underlying mechanism by in vitro–in vivo experiment technology combined with proteomics technology. First, icaritin showed a significant cytotoxic effect on HK‐2 cells, which was accompanied by increased LDH and TNF‐α in the supernatant, decreased protein expressions of Bcl‐2 and increased Bax and enhanced apoptosis of HK‐2 cells as measured by TUNEL staining. Moreover, icaritin induced obvious tubular damage and up‐regulation of BUN and CRE levels in plasma in mice. Second, intracellular uptake of icaritin was considerably higher in hOAT1‐HEK293 cells than in mock‐HEK293 cells, suggesting that icaritin might accumulate in renal cells via OAT1 uptake. Importantly, icaritin caused significant changes in the PPAR signaling pathway in HK2 cells through proteomic analysis. Then, in vitro and in vivo results verified that icaritin significantly downregulated the protein expression of PPAR‐α as well as downregulated APOB, ACSL3, ACSL4, and upregulated 5/12/15‐HETE, implying that a lipid metabolism disorder was involved in the icaritin‐induced nephrotoxicity. Finally, icaritin was found to increase the accumulation of iron and LPO levels while reducing the activity of GPX4, suggesting that ferroptosis was involved in the nephrotoxicity induced by icaritin.