Vitamin E analogues differentially inhibit human cytochrome P450 3A (CYP3A)-mediated oxidative metabolism of lithocholic acid: Impact of δ-tocotrienol on lithocholic acid cytotoxicity

Wong SY, Teo JSM, Chai SF, Yeap SL, Lau AJ

Toxicology. 2019 May 15;423:62-74. doi: 10.1016/j.tox.2019.05.005. [Epub ahead of print]

Abstract

Lithocholic acid is a cytotoxic bile acid oxidized at the C-3 position by human cytochrome P450 3A (CYP3A) to form 3-ketocholanoic acid, but it is not known whether this metabolite is cytotoxic. Tocotrienols, in their various isomeric forms, are vitamin E analogues. In the present study, the hypothesis to be tested is that tocotrienols inhibit CYP3A-catalyzed lithocholic acid 3-oxidation, thereby influencing lithocholic acid cytotoxicity. Our enzyme catalysis experiments indicated that human recombinant CYP3A5 in addition to CYP3A4, liver microsomes, and intestinal microsomes catalyzed lithocholic acid 3-oxidation to form 3-ketocholanoic acid. Liver microsomes with the CYP3A5*1/*3 and CYP3A5*3/*3 genotypes were associated with decreased lithocholic acid 3-oxidation. α-Tocotrienol, γ-tocotrienol, δ-tocotrienol, and a tocotrienol-rich vitamin E mixture, but not α-tocopherol (a vitamin E analogue), differentially inhibited lithocholic acid 3-oxidation catalyzed by liver and intestinal microsomes and recombinant CYP3A4 and CYP3A5. Compared to lithocholic acid 3-oxidation, CYP3A-catalyzed testosterone 6β-hydroxylation was inhibited to a lesser extent by α-tocotrienol, γ-tocotrienol, δ-tocotrienol, and a tocotrienol-rich vitamin Emixture. δ-Tocotrienol inhibited lithocholic acid 3-oxidation by a mixed mode. Like lithocholic acid, 3-ketocholanoic acid was also cytotoxic in human intestinal and liver cell models. δ-Tocotrienol decreased the extent of lithocholic acid 3-oxidation and this inhibition was associated with enhanced cytotoxicity in LS180 cells treated with δ-tocotrienol and lithocholic acid. Overall, vitamin E analogues inhibited in vitro lithocholic acid 3-oxidation in an isomer-dependent manner, with inhibition occurring with tocotrienols, but not α-tocopherol. The enhanced lithocholic acid toxicity by δ-tocotrienol in a human intestinal cell model warrants future investigations in vivo.

Liu X, Zhang Y, Yang X

Ecotoxicol Environ Saf. 2019 May 15;172:33-39. doi: 10.1016/j.ecoenv.2019.01.048. Epub 2019 Jan 19.

Abstract

Exposure to specific air pollutants has been demonstrated to induce damage in the brain. However, these studies ignore the effects of a combination of contaminants, and there is a high likelihood that people will be exposed to a mixture of contaminants in daily life. Our previous study showed that co-exposure to formaldehyde (FA) and PM2.5 induced damage in the mouse brain at the safe exposure level for FA or PM2.5 exposure alone, and that oxidative stress and inflammation may be involved in the toxicity mechanisms. A universal strategy to protect people exposed to FA and PM2.5 is urgently needed. To explore whether an exogenous substance could counteract the negative effects of exposure to these pollutants, we administered vitamin E (Vit E) to the experimental animals. The results showed that administration of Vit E in tandem with the FA and PM2.5 co-exposure, reduced the extent of damage to the mouse brain. Down-regulation of oxidative stress and inflammation were proposed to explain the protective effects of Vit E. This research provides a universal strategy to effectively protect people who are exposed to FA and PM2.5 simultaneously.

Farajbakhsh A, Mazloomi SM, Mazidi M, Rezaie P, Akbarzadeh M, Ahmad SP, Ferns GA, Ofori-Asenso R, Babajafari S

Eur J Clin Nutr. 2019 May 14. doi: 10.1038/s41430-019-0438-5. [Epub ahead of print]

Abstract

OBJECTIVES:

Metabolic syndrome (MetS) represents a clustering of metabolic abnormalities that are associated with an increased risk of type 2 diabetes and cardiovascular disease. We aimed to evaluate the effects of sesame oil enriched with vitamin E (vit E), sesame oil alone and sunflower oil on lipid profile, fasting blood glucose (FBG), malondialdehyde (MDA), high-sensitivity C-reactive protein (Hs-CRP), homeostatic model assessment (HOMA-IR), and blood pressure (BP) in patients with MetS.

SUBJECTS:

Overall, 75 individuals with MetS (aged 30-70 years) participated in this randomized, single-blind controlled trial. Patients were randomly allocated to: (1) Group A (n = 25): sesame oil (30 ml/day) enriched with vit E (400 mg/day), (2) Group B (n = 25): sesame oil (30 ml/day), (3) Group C (n = 25): sunflower oil (30 ml/day). Anthropometric data, dietary intake, blood pressure, and biochemical markers, including fasting serum lipids, FBG, serum insulin, MDA, and hs-CRP were measured at baseline and at week 8.

RESULTS:

In individuals in the sesame oil enriched with vit E group (Group A), there were significant reductions in serum total cholesterol (TC), triglycerides (TG), FBG, HOMA-IR, MDA, hs-CRP, high-density lipoprotein (HDL-C) systolic and diastolic BP (for all the comparison p < 0.02). Similarly, in Group B (taking sesame oil alone), TC, TG, FBG, HOMA-IR, MDA, systolic and diastolic BP were significantly improved (for all the comparison p < 0.025), while there were no significant changes in serum HDL (baseline = 35.9 ± 7.2 mg/dL vs. 36.4 ± 6.2 mg/dL, p = 0.432) and hs-CRP (baseline = 4.38 ± 1.34 mg/dL vs. week 8 = 3.96 ± 1.7 mg/dL, p = 0.057) in second group. No significant changes in any of the studied clinical and anthropometric data were found in Group C (on sunflower oil).

CONCLUSION:

Sesame oil (±vit E) was shown to beneficially affect several cardiometabolic indices (including lipids, FBG, BP, HOMA-IR, and MDA) in patients with MetS.

Gou S, Del Rio-Sancho S, Singhal M, Laubach HJ, Kalia YN

Eur J Pharm Sci. 2019 May 10;135:22-31. doi: 10.1016/j.ejps.2019.05.007. [Epub ahead of print]

Abstract

Radiation induced fibrosis is a common side-effect after radiotherapy. Pentoxifylline is reported to reverse radiation injuries when used in conjunction with D-α-tocopherol. However, pentoxifylline has a short half-life, limited oral bioavailability, and induces several systemic adverse effects. The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α –tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topically applied microparticles. Application of the pentoxifylline and D-α-tocopherol succinate containing microparticles, prepared with RESOMER® RG 502H, to laser porated skin for 48 h, resulted in simultaneous delivery of pentoxifylline (69.63 ± 6.41 μg/cm²; delivery efficiency 46.4%) and D-α-tocopherol succinate (33.25 ± 8.91 μg/cm²; delivery efficiency 22.2%). After deposition into the micropores, the poly(lactide-co-glycolide) microparticles containing pentoxifylline and D-α-tocopherol succinate could serve as an intraepidermal depot to enable sustained drug delivery after micropore closure and thereby reduce the need for repeated microporation.

Nesari A, Mansouri MT, Khodayar MJ, Rezaei M

Nutr Neurosci. 2019 May 14:1-11. doi: 10.1080/1028415X.2019.1601888. [Epub ahead of print]

Abstract

OBJECTIVE:

The ubiquitin-proteasome system plays a key role in memory consolidation. Proteasome inhibition and free radical-induced neural damage were implicated in neurodegenerative states. In this study, it was tested whether alpha-tocopherol (αT) in low and high doses could improve the long-term memory impairment induced by proteasome inhibition and protects against hippocampal oxidative stress.

METHODS:

Alpha-tocopherol (αT) (60, 200 mg/kg, i.p. for 5 days) was administered to rats with memory deficit and hippocampal oxidative stress induced by bilateral intra-hippocampal injection of lactacystin (32 ng/μl) and mitochondrial evaluations were performed for improvement assessments.

RESULTS:

The results showed that lactacystin significantly reduced the passive avoidance memory performance and increased the level of malondialdehyde (MDA), reactive oxygen species (ROS) and diminished the mitochondrial membrane potential (MMP) in the rat hippocampus. Furthermore, Intraperitoneal administration of αT significantly increased the passive avoidance memory, glutathione content and reduced ROS, MDA levels and impaired MMP.

CONCLUSIONS:

The results suggested that αT has neuroprotective effects against lactacystin-induced oxidative stress and memory impairment via the enhancement of hippocampal antioxidant capacity and concomitant mitochondrial sustainability. This finding shows a way to prevent and also to treat neurodegenerative diseases associated with mitochondrial impairment.

Sepidarkish M, Akbari-Fakhrabadi M, Daneshzad E, Yavari M, Rezaeinejad M, Morvaridzadeh M, Heshmati J

Clin Nutr. 2019 May 10. pii: S0261-5614(19)30215-8. doi: 10.1016/j.clnu.2019.05.004. [Epub ahead of print]

Abstract

BACKGROUND & AIMS:

The impact of combined omega-3 FAs and vitamin E supplementation on oxidative stress (OS) has been evaluated in several studies. However the results are inconsistent. Therefore, we performed a systematic review and meta-analysis to assess the role of omega-3 FAplus vitamin E on anti-oxidant and OS parameters.

METHODS:

We searched five databases (PubMed, Embase, Web of Sciences, Scopus and the Cochrane Central Register of Controlled Trials) from inception until March 15th 2018 for RCT covering OS parameters combined with omega-3 FAs and vitamin E. The effect of omega-3 FAs plus vitamin E combination on OS factors was determined as the standardized mean difference (SMD) calculated according to DerSimonian and Laird for the random effects model.

RESULTS:

Nine articles were included in our analyses, significant improvements were observed in trials supplementing with omega-3 FAs plus vitamin E vs placebo for total antioxidant capacity (TAC) (SMD=0.63, 95%CI: 0.31 to 0.95, P<0.001) and nitric oxide (NO) (SMD=0.55, 95%CI: 0.23 to 0.87, P<0.001). Significant reduction was observed for malondialdehyde (MDA) (SMD: -0.48, 95%CI: -0.68 to -0.28, P<0.001). However, the results of meta-analysis did not show a significant difference in levels of glutathione (GSH) (SMD=0.34, 95%CI: -0.07 to 0.75, P=0.10), superoxide dismutase (SOD) activity (SMD: 0.07, 95% CI: -0.58 to 0.73, P=0.82) and Catalase (CAT) activity (SMD: 0.74, 95% CI: -0.30 to 1.79, P=0.16).

CONCLUSION:

Co-supplementation with omega-3 FAs and vitamin E increases the levels of NO and TAC, while MDA levels decrease compared to placebo. However, the results showed no significant alterations on GSH concentrations, CAT, and SOD activities.

Elfakhri KH, Abdallah IM, Brannen AD, Kaddoumi A

Neurobiol Dis. 2019 May;125:123-134. doi: 10.1016/j.nbd.2019.01.020. Epub 2019 Jan 30.

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ) using a cell-based BBB model. Results from HTS identified etodolac and α-tocopherol as promising drugs for further investigation. Both drugs were tested separately and in combination for the purpose of targeting multiple pathways including neuroinflammation and oxidative stress. In vitro studies assessed the effects of etodolac and α-tocopherol individually and collectively for BBB integrity and Aβ transport, synaptic markers and Aβ production in APP-transfected neuronal cells, as well as effects on inflammation and oxidative stress in astrocytes. Transgenic 5XFAD mice were used to translate in vitro results of etodolac and α-tocopherol independently and with concurrent administration. Compared to either drug alone, the combination significantly enhanced the BBB function, decreased total Aβ load correlated with increased expression of major transport proteins, promoted APP processing towards the neuroprotective and non-amyloidogenic pathway, induced synaptic markers expression, and significantly reduced neuroinflammation and oxidative stress both in vitro and in vivo. Collective findings demonstrated the combination produced mixed interaction showing additive, less than additive or synergistic effects on the evaluated markers. In conclusion, this study highlights the significance of combination therapy to simultaneously target multiple disease pathways, and suggest the repurposing and combination of etodolac and α-tocopherol as a novel therapeutic strategy against AD.

Matsuo K, Watanabe T, Takenaka A

Physiol Behav. 2019 May 4;207:64-72. doi: 10.1016/j.physbeh.2019.04.026. [Epub ahead of print]

Abstract

It has been reported that the degree of anxiety-like behavior differs between inbred strains of mice, and that this phenomenon was linked to the expression levels of the oxidative stress-related genes glyoxalase 1 (Glo1) and glutathione reductase 1 (Gsr) in the brain. Therefore, we investigated whether antioxidative activity in the brain affects the Glo1 and Gsr mRNA expressions and strain-dependent anxiety-like behavior using mice fed different amounts of vitamin E. First, we measured brain Glo1 and Gsr mRNA levels and evaluated the anxiety-like behaviors presented by C57BL/6J (B6) and DBA/2C (D2) mice. We demonstrated that D2 mice presented both significantly elevated Glo1 and Gsr mRNA levels as well as more prominent anxiety-like behavior in elevated plus-maze and open field tests. Next, we fed mice from these two strains either a control, vitamin E-free, or vitamin E-supplemented diet for four weeks. Plasma, liver, and brain α-tocopherolconcentrations changed in a dose-dependent manner. However, neither brain Glo1 and Gsr mRNA levels nor anxiety-like behavior were affected by dietary vitamin E intake. These results demonstrated that while strain-dependent anxiety-like behavior in mice was related to oxidative stress-related gene expression, the regulatory mechanisms for these genes and anxiety-like behaviors were independent of antioxidative activity in the brain. Strain-dependent differences of the anxiety in mice are probably related to the anxiolytic effects of methylglyoxal, a substrate for Glo1 and Gsr.

He W, Xu Y, Ren X, Xiang D, Lei K, Zhang C, Liu D

Dig Dis Sci. 2019 May 10. doi: 10.1007/s10620-019-05657-9. [Epub ahead of print]

Abstract

BACKGROUND:

Vitamin E has been reported to have a beneficial effect on nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism of action has not yet been clearly defined.

AIM:

We aimed to evaluate the effects and mechanisms of vitamin E on lipid and glucose homeostasis both in vivo and in vitro.

METHODS:

An NAFLD model was established in C57BL/6 mice fed a 30% fructose solution for 8 weeks. Subsequently, NAFLD mice were given vitamin E (70 mg/kg) for 2 weeks. In addition, L02 cells were treated with 5 mM fructose and 100 nM vitamin E to explore the potential mechanisms of action.

RESULTS:

Vitamin E reversed the impaired glucose tolerance of fructose-treated mice. Histopathological examination showed that liver steatosis was significantly relieved in vitamin E-treated mice. These effects may be attributed to the upregulation of nuclear factor erythroid-2-related factor 2 (Nrf2), carboxylesterase 1 (CES1), and downregulated proteins involved in lipid synthesis by vitamin E treatment. In vivo, vitamin E also significantly reduced lipid accumulation in fructose-treated L02 cells, and the Nrf2 inhibitor ML385 reversed the protective effects of vitamin E.

CONCLUSION:

These data indicated that the therapeutic effects of vitamin E on lipid and glucose homeostasis may be associated with activation of the Nrf2/CES1 signaling pathway.