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. 2019 Jul 25:10:782.
doi: 10.3389/fphar.2019.00782. eCollection 2019.

The Essential Oils and Eucalyptol From Artemisia vulgaris L. Prevent Acetaminophen-Induced Liver Injury by Activating Nrf2-Keap1 and Enhancing APAP Clearance Through Non-Toxic Metabolic Pathway

Zhihui Jiang  1 , Xiao Guo  1 , Kunpeng Zhang  1 , Ganesh Sekaran  2   3 , Baorui Cao  1 , Qingqing Zhao  1 , Shouquan Zhang  4 , Gordon M Kirby  5 , Xiaoying Zhang  1   2   5
Affiliations

The Essential Oils and Eucalyptol From Artemisia vulgaris L. Prevent Acetaminophen-Induced Liver Injury by Activating Nrf2-Keap1 and Enhancing APAP Clearance Through Non-Toxic Metabolic Pathway

Zhihui Jiang et al. Front Pharmacol. .

Abstract

Artemisia has long been used in traditional medicine and as a food source for different functions in eastern Asia. Artemisia vulgaris L. (AV) is a species of the genus Artemisia. Essential oils (EOs) were extracted from AV by subcritical butane extraction. EO contents were detected by electronic nose and headspace solid-phase microextraction coupled with gas chromatography (HS-SPME-GC-MS). To investigate the hepatoprotective effects, mice subjected to liver injury were treated intragastrically with EOs or eucalyptol for 3 days. Acetaminophen (APAP) alone caused severe liver injury characterized by significantly increased serum AST and ALT levels, ROS and hepatic malondialdehyde (MDA), as well as liver superoxide dismutase (SOD) and catalase (CAT) depletions. EOs significantly attenuated APAP-induced liver damages. Further study confirmed that eucalyptol is an inhibitor of Keap1, the affinity K D of eucalyptol and Keap1 was 1.42 × 10-5, which increased the Nrf2 translocation from the cytoplasm into the mitochondria. The activated Nrf2 increased the mRNA expression of uridine diphosphate glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), also inhibiting CYP2E1 activities. Thus, the activated Nrf2 suppressed toxic intermediate formation, promoting APAP hepatic non-toxicity, whereby APAP was metabolized into APAP-gluc and APAP-sulf. Collectively, APAP non-toxic metabolism was accelerated by eucalyptol in protecting the liver against APAP-induced injury, indicating eucalyptol or EOs from AV potentials as a natural source of hepatoprotective agent.

Keywords: Artemisia vulgaris; Nrf2-Keap1; acetaminophen; essential oil; eucalyptol; liver.

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Figures

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Graphical Abstract
Figure 1
Figure 1
Species identification of sample 2 by phylogenetic tree and ITS2 secondary structure. (A) Phylogenetic tree of the four Artemisia species constructed with the ITS2 sequences using the neighbor-joining (NJ) method; (B) ITS2 secondary structure.
Figure 2
Figure 2
Component analysis of Artemisia vulgaris L. essential oils (AV-EOs). (A) Polar plot display of sensor values of EOs from AV at 57 s given by the cursor in the measurement window; (B) principal component analysis (PCA); (C) loading (Lo) analysis; W1C (aromatic), W5S (broadrange), W3C (aromatic), W6S (hydrogen), W5C (arom-aliph), W1S (broad-methane), W1W (sulphur-organic), W2S (broad-alcohol), W2W (sulph-chlor), W3S (methane-aliph); (D) the headspace solid-phase microextraction coupled with gas chromatography (HS-SPME-GC-MS) diagram of AV.
Figure 3
Figure 3
Effect of essential oil and eucalyptol on the acetaminophen (APAP)-induced liver changes and serum biomarkers of liver toxicity in mice. (A–E) The liver changes in mice. (A) Control group; (B) APAP treatment group, circle means cytoplasmic vacuolation; (C) APAP-EO treatment group; (D) APAP-EU treatment group; (E) APAP-NAC treatment group; (F) EO treatment group; (G) EU treatment group; (H) the activity of ALT and AST. n = 6, bars that do not share a common letter (a, b, c) were considered significantly different from each other (p < 0.05).
Figure 4
Figure 4
Effects of essential oil and eucalyptol on the APAP-induced oxidative stress parameters. a, b, c different letters indicate statistically different groups (p < 0.05).
Figure 5
Figure 5
mRNA expression levels of oxidative stress-related genes . a, b, c, d different letters indicate statistically different groups (p < 0.05).
Figure 6
Figure 6
Effects of eucalyptol on the APAP metabolic disposition. APAP: APAP treatment group; APAP+EU: EU was intragastrically administrated after APAP treatment group; APAP+NAC: NAC was oral administration after APAP treatment group. EU: EU was intragastrically administrated. a, b, c different letters indicate statistically different groups (p < 0.05).
Figure 7
Figure 7
Effect of eucalyptol on nuclear factor erythroid 2-related factor 2 (Nrf2) expression. (A) eucalyptol docking with Keap1; (B) binding signal of Keap1 and eucalyptol (RU); (C) mRNA levels of Nrf2; (D) protein levels of Nrf2 in nuclear and cytosolic. a, b, c different letters indicate statistically different groups (p < 0.05).
Figure 8
Figure 8
Mechanism by which eucalyptol protects APAP induced liver injury.
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References

    1. Asrani S. K., Devarbhavi H., Eaton J., Kamath P. S. (2018). Burden of liver diseases in the world. J. Hepatol. 70, 151–171. 10.1016/j.jhep.2018.09.014 - DOI - PubMed
    1. Cao L., Kwara A., Greenblatt D. J. (2017). Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. Int. J. Clin. Pharm-Net. 69, 12, 1762–1772. 10.1111/jphp.12812 - DOI - PMC - PubMed
    1. Chen M., Li X., Shi Q., Zhang Z., Xu S. (2019). Hydrogen sulfide exposure triggers chicken trachea inflammatory injury through oxidative stress-mediated FOS/IL8 signaling. J. Hazard. Mater. 368, 243–254. 10.1016/j.jhazmat.2019.01.054 - DOI - PubMed
    1. Cho K. H. (2012). 1,8-cineole protected human lipoproteins from modification by oxidation and glycation and exhibited serum lipid-lowering and anti-inflammatory activity in zebrafish. BMB Rep. 45 (10), 565–570. 10.5483/BMBRep.2012.45.10.044 - DOI - PubMed
    1. Dennis G., Jr., Sherman B. T., Hosack D. A., Yang J., Gao W., Lane H. C., et al. (2003). DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4 (5), P3. 10.1186/gb-2003-4-9-r60 - DOI - PubMed