Involvement of NF-κB in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats

Abstract

Previous studies reported that sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae, HRP) exhibits hepatoprotective effects via its anti-inflammatory and antioxidant properties as well as its inhibitory effects on collagen synthesis. However, it is unclear whether this hepatoprotective effect is also achieved by regulating liver drug metabolism enzyme pathways. Herein, we examined the regulatory effect of HRP on cytochrome P450 3A (CYP3A) in rats with immune liver injury, and explored the molecular mechanism of its hepatoprotective effect. Rat models of immunological liver injury were induced by intravenous injections of Bacillus Calmette-Guerin (BCG; 125 mg kg-1 ; 2 wks). Specific protein levels were detected by ELISA or western blot, and CYP3A mRNA expression was detected by RT-PCR. High-performance liquid chromatography (HPLC) detected relative changes in CYP3A metabolic activity based on the rates of 1-hydroxylation of the probe drug midazolam (MDZ). BCG pretreatment (125 mg kg-1) significantly down-regulated liver CYP3A protein expression compared with the control, metabolic activity, and transcription levels while up-regulating liver NF-κB, IL-1β, TNF-α and iNOS. HRP intervention (ED 50 : 78 mg kg-1) moderately reversed NF-κB, inflammatory cytokines, and iNOS activation in a dose-dependent manner (P < 0.05), and suppressed CYP3A down-regulation (P < 0.05); thereby partially alleviating liver injury. During immune liver injury, HRP may reverse CYP3A downregulation by inhibiting NF-κB signal transduction, and protect liver function, which involves regulation of enzymes transcriptionally, translationally and post-translationally. The discovery that NF-κB is a molecular target of HRP may initiate the development and optimization of a clinical therapeutic approach to mitigate hepatitis B and other immunity-related liver diseases.

Hippophae rhamnoides reverses decreased CYP2D6 expression in rats with BCG-induced liver injury

“…Immuno-stimulation with BCG downregulated liver CYP2D6, and HRP intervention reversed this effect in a dose-dependent manner to protect liver metabolic function. Sea buckthorn granules are mainly composed of sea buckthorn fruits rich in vitamins, carotenoids, flavonoids, essential oils, carbohydrates, organic acids, amino acids, and minerals 1 . HRP administration alone did not exhibit any appreciable effect on the expression and metabolic activity of liver CYP2D6, indicating that HRP does not normally induce or inhibit CYP2D6.…”

“…We previously demonstrated the regulatory effect of NF-κB on CYP2E1 in Bacille Calmette–Guerin (BCG)-induced immune liver injury 28 . The sea buckthorn was also shown to reverse the downregulation of CYP3A by inhibiting NF-κB signal transduction in cases of immune liver injury 1 . The mRNA expression of CYP2D6 strongly correlated with enzyme activity in liver tissues of more than 130 non-weak metabolizers (r = 0.95), similar to that of CYP3A4 (r = 0.90) 25 .…”

“…Hippophae rhamnoides (HRP), a well-known medicinal and edible plant, also called sea buckthorn, is used as a new treatment strategy for injury and fibrosis of the liver, a major metabolic organ 1 , 2 . However, the sea buckthorn’s ability to regulate imbalanced metabolic enzymes associated with liver diseases that cause immune-mediated liver damage, such as viral hepatitis, is not fully understood.…”

New insights into the downregulation of cytochrome P450 2E1 via nuclear factor κB-dependent pathways in immune-mediated liver injury

“…Herein, we used the Bacillus Calmette–Guerin (BCG) vaccine to induce autoimmune liver injury in rats to evaluate the role of reduced CYP2E1 expression. BCG infection activates macrophages and T lymphocytes in the liver, releasing pro-inflammatory cytokines such as interleukin-1β, tumour necrosis factor-α, and interferon-γ, and has been shown to be a cell-mediated immune response [ 5 , 16 ]. Based on our prior investigations, we explored the mechanisms underlying NF-κB-mediated regulation of PKC/CREB phosphorylation and inducible nitric oxide synthase (iNOS)-mediated nitration.…”

Metabolomic Profiling Reveals Protective Effects and Mechanisms of Sea Buckthorn Sterol against Carbon Tetrachloride-Induced Acute Liver Injury in Rats

“…Furthermore, sea buckthorn inhibits CYP3A down-regulation during immune liver injury, primarily through the transcriptional regulation and post-translational nitration of enzyme proteins. This mechanism is also applicable to alcoholic liver injury and non-alcoholic fatty liver [ 13 ]. On the other hand, many investigations demonstrate that SO 2 exposure causes a significant change in the glutathione redox system of rats.…”