Substrate-dependent Inhibition of Hypericin on Human Carboxylesterase 2: Implications for Herb-drug Combination

Dalong Wang; Tingting Zhao; Shan Zhao; Jing Chen; Tongyi Dou; Guangbo Ge; Changyuan Wang; Huijun Sun; Kexin Liu; Qiang Meng; Jingjing Wu

doi:10.2174/1389200223666220202093303

Substrate-dependent Inhibition of Hypericin on Human Carboxylesterase 2: Implications for Herb-drug Combination

Curr Drug Metab. 2022;23(1):38-44. doi: 10.2174/1389200223666220202093303.

Authors

Dalong Wang^{1

2}, Tingting Zhao^{1

2}, Shan Zhao³, Jing Chen⁴, Tongyi Dou⁴, Guangbo Ge⁵, Changyuan Wang^{1

2}, Huijun Sun^{1

2}, Kexin Liu^{1

2}, Qiang Meng^{1

2}, Jingjing Wu^{1

2}

Affiliations

¹ Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
² Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China.
³ Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
⁴ School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, China.
⁵ Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

PMID: 35114918
DOI: 10.2174/1389200223666220202093303

Abstract

Background: Hypericin is the main active ingredient of St. John's wort, a Chinese herb commonly used for treating depression. Previous studies shown that hypericin can strongly inhibit human cytochrome P450 (CYP) enzyme activities; however, its potential interactions that inhibit human carboxylesterases 2 (hCE2) are unclear.

Purpose: This study aimed to investigate the inhibitory effect of hypericin on hCE2.

Methods: The inhibition mechanism 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 (K_i) value were determined. The inhibition of hypericin on hCE2 in living cells was discussed. The risk of herb-drug interactions (HDI) of hypericin in vivo was predicted by estimating the area under the drug concentration-time curve (AUC) in the presence or absence of hypericin. 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 K_i values were estimated as 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 coadministration 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 regarding the combination of hypericin-containing herbs and drugs metabolized by hCE2 are of considerable clinical significance.

Keywords: CPT-11; HDI; Hypericin; NCEN; hCE2; inhibition.

MeSH terms

Anthracenes*
Drug Combinations
Herb-Drug Interactions
Humans
Hypericum*
Irinotecan
Molecular Docking Simulation
Perylene / analogs & derivatives

Substances

Anthracenes
Drug Combinations
Perylene
Irinotecan
hypericin

Abstract

MeSH terms

Substances

Grants and funding