Accumulated LPS induced by colitis altered the activities of vitamin D-metabolizing hydroxylases and decreased the generation of 25-hydroxyvitamin D.

It is generally accepted that low vitamin D (VD) levels are associated with a high prevalence factor for Inflammatory bowel disease (IBD). IBD patients have observed higher levels of lipopolysaccharide (LPS), ALT, and AST than healthy people. Gut-derived LPS causes inflammatory injury in the liver and kidney. The VD-metabolizing mechanism is involved in the liver and kidney, which means IBD might impact VD metabolism. However, whether IBD affects VD metabolism has not been studied. In vitro LPS resulted in decreased CYP2R1 in liver cells as well as decreased CYP27B1 and increased CYP24A1 in kidney cells, revealing that LPS changed the activities of several hydroxylases. Mice with acute colitis had an increased LPS in serum and liver with mild hepatic injuries, while mice with chronic colitis had a significant elevation of LPS in serum, liver, and kidney with hepatorenal injuries. Thus, the liver hydroxylase for VD metabolism would be the first to be affected in IBD. Consequently, serum 25-hydroxyvitamin D declined dramatically with a significant elevation of 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D. Unchanged serum levels of 1,25-dihydroxyvitamin D might be the result of other factors in vivo. In acute colitis, a small dosage (4 IU/day) of cholecalciferol could protect the colon, decrease the serum level of LPS, and finally increase serum 25-hydroxyvitamin D. However, this improvement of cholecalciferol was fading in chronic colitis. These results suggested that VD supplementations for preventing and curing IBD in the clinic should consider hepatorenal hydroxylases and be employed as soon as possible for a better outcome.

The Association between CYP2C19 Genetic Polymorphism and Prognosis in Patients Receiving Endovascular Therapy.

Background: Potentially substantial impacts on the prognosis have been observed in individuals undergoing endovascular treatment due to cytochrome P450 2c19 (CYP2C19) polymorphism. In an attempt to improve prognosis and lower the recurrence rate, this study investigated the CYP2C19 polymorphism in acute ischemic stroke patients. Materials and Methods: A retrospective analysis was performed on 292 patients with cerebral infarction who had acute endovascular recanalization at the Department of Neurology of Chongqing Hospital of Traditional Chinese Medicine between May 2017 and 2019. The patients were categorized into rapid-, medium-, and slow-metabolism groups based on CYP2C19 gene polymorphism, and their prognosis was monitored. In addition, the prognosis of 188 patients selectively receiving carotid artery stenting at a selected time was also observed. Results: Among the 292 cerebral infarction cases receiving acute endovascular recanalization, the patients in the CYP2C19 rapid-metabolism group regularly took clopidogrel and aspirin combined with antiplatelet therapy and suffered from reoccurrence of apoplexy and cerebral hemorrhage; the 90-day good prognosis had a statistical difference (P < 0.05, prognostic assessment includes hospitalization and 6 months after discharge) and the other adverse events had no statistical difference (including mortality). The 188 patients selectively receiving carotid artery stenting had a recurrence of apoplexy, cerebral hemorrhage, and restenosis rate with a statistical difference (P < 0.05), and the other adverse events had no statistical difference. Conclusions: In conclusion, the findings of the current study indicate that irrespective of whether patients are undergoing selective carotid artery stenting or acute endovascular recanalization, those with rapid CYP2C19 metabolism have a significantly lower likelihood of experiencing adverse prognostic events compared to those with intermediate and slow metabolism. Furthermore, this group also has a more favorable prognosis than the other two groups.

Assessment of Pharmacokinetic Effects of Herbal Medicines on Escitalopram.

Purpose: Herbal medicines are occasionally used in combination with conventional antidepressants to mitigate various depression-associated symptoms. However, there is limited information on herb-antidepressant interactions. In this study, we investigated the pharmacokinetic (PK) effects of four herbal medicines (Gami-soyosan, Banhasasim-tang, Ojeok-san, and Bojungikgi-tang) on escitalopram, a commonly used antidepressant. Patients and Methods: In this open-label, fixed-sequence, three-period, crossover study, 18 participants were enrolled and divided into two groups. Each group received a 10 mg oral dose of escitalopram in period 1. Participants took escitalopram once daily and their assigned herbal medicines thrice a day for 7 d in periods 2 (group 1: Gami-soyosan, group 2: Ojeok-san) and 3 (group 1: Banhasasim-tang; group 2: Bojungikgi-tang). The primary endpoints were Cmax,ss and AUCtau,ss of escitalopram. Cmax,ss and AUCtau,ss in period 1 were obtained using nonparametric superposition from single-dose data. The PK endpoints were classified according to the CYP2C19 phenotype. Results: Of 18 participants, 16 completed the study. Systemic exposure to escitalopram resulted in a minor increase in the presence of each herbal medicine. The geometric mean ratios (GMRs, combination with herbal medicines/escitalopram monotherapy) and their 90% confidence intervals (CIs) for Cmax,ss and AUCtau,ss were as follows: Gamisoyosan- 1.1454 (0.9201, 1.4258) and 1.0749 (0.8084, 1.4291), Banhasasim-tang-1.0470 (0.7779, 1.4092) and 1.0465 (0.7035, 1.5568), Ojeok-san-1.1204 (0.8744, 1.4357) and 1.1267 (0.8466, 1.4996), and Bojungikgi-tang-1.1264 (0.8594, 1.4762) and 1.1400 (0.8515, 1.5261), respectively. Furthermore, no significant differences in the GMRs of Cmax,ss and AUCtau,ss were observed across different CYP2C19 phenotypes in any of the groups. Conclusion: The co-administration of escitalopram with Gami-soyosan, Banhasasim-tang, Ojeok-san, or Bojungikgi-tang did not exert significant PK effects on escitalopram. These findings provide valuable insights into the safe use of herbal medicines along with escitalopram.

Influence of Different Plant Extracts on CYP-Mediated Skatole and Indole Degradation in Pigs.

One of the primary substances responsible for the unpleasant odor in boar meat is skatole. Enzymes belonging to the cytochrome P450 (CYP) family play a pivotal role in the hepatic clearance of skatole. This study aimed to investigate the impact of oregano essential oil (OEO), Schisandra chinensis extract (SC), and garlic essential oil (GEO) on hepatic CYP2E1 and CYP2A activity in pigs. In three consecutive trials, cannulated castrated male pigs were provided with a diet containing 0.2-0.3% of one of these plant extracts. Following a 14-day feeding period, the animals were slaughtered, and liver and fat samples were collected. The findings indicate that the activities of CYP2E1 were unaffected by any treatment. However, GEO treatment demonstrated a significant reduction in CYP2A activity (p < 0.05). Pigs treated with GEO also exhibited a notable increase in skatole concentrations in both plasma and adipose tissue. In contrast, animals fed SC displayed elevated skatole concentrations in plasma but not in fat tissue. OEO did not influence skatole concentrations in either blood or fat. Furthermore, the study revealed that a supplementation of 6 g GEO per animal per day induced a significant increase in skatole concentrations in blood plasma within 24 h.

Interactions studies of CYP2D6 with quercetin and hyperoside by spectral analysis and molecular dynamics simulations.

Some ingredients from herbal medicine can significantly affect the activity of CYP2D6, thus leading to serious interactions between herbs and drugs. Quercetin and hyperoside are active ingredients widely found in vegetables, fruits, and herbal medicines. Quercetin and hyperoside have many biological activities. In this work, the characteristic bindings of CYP2D6 with quercetin/hyperoside are revealed by multi-spectroscopy analysis, molecular docking, and molecular dynamics simulations. The fluorescence of CYP2D6 is statically quenched by quercetin and hyperoside. The binding constant (Ka ) values of CYP2D6-quercetin/hyperoside range from 104 L mol-1 , which indicates that these two flavonoids bind moderately to CYP2D6. Meanwhile, quercetin has a stronger quenching ability to CYP2D6 than that of hyperoside. The secondary structure of CYP2D6 is obviously changed by binding with quercetin/hyperoside. The docking results reveal that the quercetin/hyperoside enters the active site of CYP2D6 near heme and binds to CYP2D6 by hydrogen bonds and van der Waals forces. The molecular dynamics simulation results indicate that the binding of quercetin/hyperoside can stabilize the two complexes, enhance the flexibility of CYP2D6 backbone atoms, and make a more unfolded and looser structure of CYP2D6.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes.

PURPOSE: Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)-positive breast cancer patients under different genotypes. MATERIALS AND METHODS: CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. RESULTS: A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). CONCLUSION: Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

Alcohol-induced liver injury in signalling pathways and curcumin's therapeutic potential.

Confronting the profound public health concern of alcohol-induced liver damage calls for inventive therapeutic measures. The social, economic, and clinical ramifications are extensive and demand a comprehensive understanding. This thorough examination uncovers the complex relationship between alcohol intake and liver damage, with a special emphasis on the pivotal roles of the Toll-like receptor 4 (TLR4)/NF-κB p65 and CYP2E1/ROS/Nrf2 signalling networks. Different alcohol consumption patterns, determined by a myriad of factors, have significant implications for liver health, leading to a spectrum of adverse effects. The TLR4/NF-κB p65 pathway, a principal regulator of inflammation and immune responses, significantly contributes to various disease states when its balance is disrupted. Notably, the TLR4/MD-2-TNF-α pathway has been linked to non-alcohol related liver disease, while NF-κB activation is associated with alcohol-induced liver disease (ALD). The p65 subunit of NF-κB, primarily responsible for the release of inflammatory cytokines, hastens the progression of ALD. Breakthrough insights suggest that curcumin, a robust antioxidant and anti-inflammatory compound sourced from turmeric, effectively disrupts the TLR4/NF-κB p65 pathway. This heralds a new approach to managing alcohol-induced liver damage. Initial clinical trials support curcumin's therapeutic potential, highlighting its ability to substantially reduce liver enzyme levels. The narrative surrounding alcohol-related liver injury is gradually becoming more intricate, intertwining complex signalling networks such as TLR4/NF-κB p65 and CYP2E1/ROS/Nrf2. The protective role of curcumin against alcohol-related liver damage marks the dawn of new treatment possibilities. However, the full realisation of this promising therapeutic potential necessitates rigorous future research to definitively understand these complex mechanisms and establish curcumin's effectiveness and safety in managing alcohol-related liver disorders.

Correlation of CYP2R1 gene promoter methylation with circulating vitamin D levels among healthy adults.

Background & objectives: Despite being a tropical country, vitamin D deficiency is highly prevalent in India with studies indicating 40-99 per cent prevalence. Apart from calcium and phosphate metabolism, vitamin D is involved in cell cycle regulation, cardiovascular, hepatoprotection. The metabolism of vitamin D is regulated by vitamin D tool genes (CYP2R1/CYP27B1/CYP24A1/VDR). The promoter regions of some of these genes have CpG islands, making them prone to methylation induced gene silencing, which may cause a reduction in circulating vitamin D levels. Epigenetic basis of vitamin D deficiency is yet to be studied in India, and hence, this pilot study was aimed to analyze whether methylation levels of CYP2R1 gene were correlated with the levels of 25(OH)D in healthy, adult individuals in Indian population. Methods: In this cross-sectional study, healthy adults of 18-45 yr of age with no history of malabsorption, thyroidectomy, chronic illness or therapeutic vitamin D supplementation were recruited. DNA methylation analysis was carried out by methylation specific quantitative PCR. Serum calcium, phosphate and vitamin D levels were also quantified. Statistical analysis was done by R 4.0.5 software. Results: A total of 61 apparently healthy adults were analyzed. The serum vitamin D levels did not correlate with CYP2R1 methylation levels in our study population. Significant positive correlation was observed between age and serum vitamin D levels. Significant association of gender was found with CYP2R1 methylation levels. Interpretation & conclusions: This study found no significant correlation between levels of CYP2R1 methylation and circulating 25(OH)D deficiency. Further studies on the Indian population having a larger sample size including entire vitamin D tool genes, among different ethnic groups may be conducted to elucidate molecular etiology of circulating 25(OH)D deficiency. The high prevalence of normal serum calcium and phosphate levels among vitamin D deficient subjects in this study coupled with the strikingly high prevalence of the deficiency at the national level, may suggest the need to revise the cut-off criteria for vitamin D deficiency in the Indian population.

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

Enzymatic activity of 38 CYP2C9 genotypes on ibuprofen.

BACKGROUND AND OBJECTIVE: Ibuprofen, a common non-steroidal anti-inflammatory drug, is used clinically for pain relief and antipyretic treatment worldwide. However, regular or long-term use of ibuprofen may lead to a series of adverse reactions, including gastrointestinal bleeding, hypertension and kidney injury. Previous studies have shown that CYP2C9 gene polymorphism plays an important role in the elimination of various drugs, which leads to the variation in drug efficacy. This study aimed to evaluate the effect of 38 CYP2C9 genotypes on ibuprofen metabolism. METHODS: Thirty-eight recombinant human CYP2C9 microsomal enzymes were obtained using a frugiperda 21 insect expression system according to a previously described method. Assessment of the catalytic function of these variants was completed via a mature incubation system: 5 pmol CYP2C9*1 and 38 CYP2C9 variants recombinant human microsomes, 5 µL cytochrome B5, ibuprofen (5-1000 µM), and Tris-HCl buffer (pH 7.4). The ibuprofen metabolite contents were determined using HPLC analysis. HPLC analysis included a UV detector, Plus-C18 column, and mobile phase [50% acetonitrile and 50% water (containing 0.05% trifluoroacetic acid)]. The kinetic parameters of the CYP2C9 genotypes were obtained by Michaelis-Menten curve fitting. RESULTS: The intrinsic clearance (CLint) of eight variants was not significantly different from CYP2C9*1; four CYP2C9 variants (CYP2C9*38, *44, *53 and *59) showed significantly higher CLint (increase by 35%-230%) than that of the wild-type; the remaining twenty-six variants exhibited significantly reduced CLint (reduced by 30%-99%) compared to that of the wild-type. CONCLUSION: This is the first systematic evaluation of the catalytic characteristics of 38 CYP2C9 genotypes involved ibuprofen metabolism. Our results provide a corresponding supplement to studies on CYP2C9 gene polymorphisms and kinetic characteristics of different variants. We need to focus on poor metabolizers (PMs) with severely abnormal metabolic functions, because they are more susceptible to drug exposure.

Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in C. elegans.

Oxidative stress is a contributing factor to Parkinson's disease (PD). Considering the prevalence of sporadic PD, environmental exposures are postulated to increase reactive oxygen species and either incite or exacerbate neurodegeneration. We previously determined that exposure to the common soil bacterium, Streptomyces venezuelae (S. ven), enhanced oxidative stress and mitochondrial dysfunction in Caenorhabditis elegans, leading to dopaminergic (DA) neurodegeneration. Here, S. ven metabolite exposure in C. elegans was followed by RNA-Seq analysis. Half of the differentially identified genes (DEGs) were associated with the transcription factor DAF-16 (FOXO), which is a key node in regulating stress response. Our DEGs were enriched for Phase I (CYP) and Phase II (UGT) detoxification genes and non-CYP Phase I enzymes associated with oxidative metabolism, including the downregulated xanthine dehydrogenase gene, xdh-1. The XDH-1 enzyme exhibits reversible interconversion to xanthine oxidase (XO) in response to calcium. S. ven metabolite exposure enhanced XO activity in C. elegans. The chelation of calcium diminishes the conversion of XDH-1 to XO and results in neuroprotection from S. ven exposure, whereas CaCl2 supplementation enhanced neurodegeneration. These results suggest a defense mechanism that delimits the pool of XDH-1 available for interconversion to XO, and associated ROS production, in response to metabolite exposure.

Cardioprotective mechanisms of cytochrome P450 derived oxylipins from ω-3 and ω-6 PUFAs.

The seminal discovery that cytochrome P450 enzymes (CYPs) can oxidize polyunsaturated fatty acids (PUFAs) sparked a new area of research aimed at discovering the role of these metabolites in cardiac physiology and pathophysiology. CYPs metabolize arachidonic acid, an ω-6 PUFA, to alcohols and epoxides with the latter providing cardioprotection following myocardial infarction, hypertrophy, and diabetes-induced cardiomyopathy through their anti-inflammatory, vasodilatory and antioxidant properties. Despite their protective properties, the use of EETs as therapeutic agents is hampered mainly by their rapid hydrolysis to less active vicinal diols by soluble epoxide hydrolase (sEH). Several approaches have been investigated to prolong EET signaling effects using small molecule sEH inhibitors, chemically and biologically stable analogs of EETs and more recently, through the development of an sEH vaccine. Alternatively, research investigating the cardioprotective outcomes of ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly focused on dietary intake or supplementation studies. EPA and DHA have overlapping but distinct effects on myocardial function and merit separate studies to fully understand their mechanism of cardiac protection. In contrast to EETs, relatively fewer studies examined the protective mechanisms of EPA and DHA derived epoxides to determine if some protective effects are in part due to the CYP mediated downstream metabolites. The actions of CYPs on PUFAs generate potent oxylipins utilizing diverse cardioprotective mechanisms and the extent of their full potential will be important for the future development of therapeutics to prevent or treat cardiovascular disease.

IUPHAR - invited review - Ibogaine - A legacy within the current renaissance of psychedelic therapy.

Ibogaine is a powerful psychoactive substance that not only alters perception, mood and affect, but also stops addictive behaviors. Ibogaine has a very long history of ethnobotanical use in low doses to combat fatigue, hunger and thirst and, in high doses as a sacrament in African ritual contexts. In the 1960's, American and European self-help groups provided public testimonials that a single dose of ibogaine alleviated drug craving, opioid withdrawal symptoms, and prevented relapse for weeks, months and sometimes years. Ibogaine is rapidly demethylated by first-pass metabolism to a long-acting metabolite noribogaine. Ibogaine and its metabolite interact with two or more CNS targets simultaneously and both drugs have demonstrated predictive validity in animal models of addiction. Online forums endorse the benefits of ibogaine as an "addiction interrupter" and present-day estimates suggest that more than ten thousand people have sought treatment in countries where the drug is unregulated. Open label pilot studies of ibogaine-assisted drug detoxification have shown positive benefit in treating addiction. Ibogaine, granted regulatory approval for human testing in a Phase 1/2a clinical trial, joins the current landscape of psychedelic medicines in clinical development.

Comparison of calcifediol with vitamin D for prevention or cure of vitamin D deficiency.

Vitamin D deficiency remains prevalent, with about 7% of the world's population living with severe vitamin D deficiency and about one third with mild deficiency. We compare the relative merits of calcifediol or 25-hydroxyvitamin D (25OHD) compared to vitamin D itself for supplementation as to prevent or cure vitamin D deficiency. The intestinal absorption of calcifediol is nearly 100% and thus higher than that of vitamin D itself. Moreover, calcifediol is absorbed by the intestinal cells and transported through the portal vein and thus immediately accessible to the circulation, while vitamin D is transported with chylomicrons through the lymph system. Therefore, in case of fat malabsorption or after bariatric surgery, calcifediol is much better absorbed in comparison with vitamin D itself. Serum 25OHD increases linearly with increasing doses of calcifediol, whereas serum 25OHD reaches a plateau when higher oral doses of vitamin D are used. Calcifediol, on a weight basis, is about 3 times more potent than vitamin D in subjects with mild vitamin D deficiency. This potency is even 6-8 times higher than vitamin D when baseline serum 25OHD is higher or when large doses are compared. In conclusion, calcifediol is an alternative option to correct vitamin D deficiency and may even be the preferred strategy in case of intestinal fat malabsorption, after bariatric surgery or in case of other conditions with suspected impaired 25-hydroxylase activity in the liver.

The palliative effect of mulberry leaf and olive leaf ethanolic extracts on hepatic CYP2E1 and caspase-3 immunoexpression and oxidative damage induced by paracetamol in male rats.

This study investigated the possible protective role of mulberry leaf (MLE) and olive leaf (OLE) ethanolic extracts against paracetamol (PTL)-induced liver injury in rats compared to silymarin as a reference drug. Initially, MLE and OLE were characterized using gas chromatography-mass spectrometry (GC/MS). Then, forty male Sprague Dawley rats were divided into five groups: the negative control group orally received distilled water for 35 days, the PTL-treated group (PTG) received 500 mg PTL/kg b. wt. for 7 days, the MLE-treated group (MLTG) received 400 mg MLE/kg b. wt., the OLE-treated group (OLTG) received 400 mg OLE/kg b. wt., and the silymarin-treated group (STG) received 100 mg silymarin/kg b. wt. The last three groups received the treatment for 28 days, then PTL for 7 days. The GC-MS characterization revealed that MLE comprised 19 constituents dominated by ethyl linoleate, phytol, hexadecanoic acid, ethyl ester, and squalene. Moreover, OLE comprised 30 components, and the major components were 11-eicosenoic acid, oleic acid, phytol, and à-tetralone. MLE and OLE significantly corrected the PTL-induced normocytic normochromic anemia, leukocytosis, hypercholesterolemia, and hypoproteinemia. Moreover, the MLE and OLE pretreatment considerably suppressed the PTL-induced increment in serum levels of hepatic enzymes, including alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. Furthermore, the PTL-induced depletion in antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, and the rise in hepatic malondialdehyde content were significantly reversed by the MLE and OLE pretreatment. Besides, MLE and OLE pretreatment significantly protected the hepatic tissue against PTL-induced DNA damage, pathological perturbations, and increased caspase 3 and CYP2E1 immunoexpression. Of note, OLTG showed better enhancement of most indices rather than MLTG. Conclusively, these findings imply that OLE, with its antioxidant and antiapoptotic capabilities, is superior to MLE in protecting against PTL-induced liver injury.

Artemisia annua L. Extracts Irreversibly Inhibit the Activity of CYP2B6 and CYP3A4 Enzymes.

Artemisia annua L. has long been known for its medicinal properties and isolation of ingredients whose derivatives are used for therapeutic purposes. The CYP2B6 and CYP3A4 enzymes belong to a large family of cytochrome P450 enzymes. These enzymes are involved in the metabolism of drugs and other xeonobiotics. It is known that various compounds can induce or inhibit the activity of these enzymes. The aim of this study was to investigate the nature of the inhibitory effect of Artemisia annua extract on CYP2B6 and CYP3A4 enzymes, as well as the type of inhibition, the presence of reversible or pseudo-irreversible inhibition, and the possible heme destruction. The methanolic extract of Artemisia annua showed an inhibitory effect on CYP2B6 (by almost 90%) and CYP3A4 enzymes (by almost 70%). A significant decrease in heme concentration by 46.8% and 38.2% was observed in different assays. These results clearly indicate that the studied plant extracts significantly inhibited the activity of CYP2B6 and CYP3A4 enzymes. Moreover, they showed irreversible inhibition, which is even more important for possible interactions with drugs and dietary supplements.

Elucidation of Natural Components of Gardenia thunbergia Thunb. Leaves: Effect of Methanol Extract and Rutin on Non-Alcoholic Fatty Liver Disease.

The rising prevalence of non-alcoholic fatty liver disease NAFLD has strained the healthcare system. Natural products could solve this problem, so the current study focused on the impact of G. thunbergia Thunb. against this ailment. LC-ESI-MS/MS revealed the phytochemical profile of the methanol extract from Gardenia thunbergia leaves (GME). Forty-eight compounds were tentatively identified, and stigmasterol, fucosterol, ursolic acid, and rutin were isolated. The separation of the last three compounds from this plant had not before been achieved. The anti-NAFLD effect of the methanol extract of the leaves of G. thunbergia, and its major metabolite, rutin, was assessed in mice against high-fructose diet (HFD)-induced obesity. Male mice were allocated into nine groups: (1) saline (control), (2) 30% fructose (diseased group), (3) HFD, and 10 mg/kg of simvastatin. Groups 4-6 were administered HFD and rutin 50, 75, and 100 mg/kg. Groups (7-9) were administered HFD and methanol extract of leaves 100, 200, and 300 mg/kg. Methanol extract of G. thunbergia leaves at 200 mg/kg, and rutin at 75 mg/kg significantly reduced HFD-induced increments in mice weight and hepatic damage indicators (AST and ALT), steatosis, and hypertrophy. The levels of total cholesterol, LDL-C, and triglycerides in the blood decreased. In addition, the expressions of CYP2E1, JNK1, and iNOS in the diseased mice were downregulated. This study found that GME and rutin could ameliorate NAFLD in HFD-fed mice, with results comparable to simvastatin, validating G. thunbergia's hepatoprotective effects.

The analysis of methylxanthine fractions obtained from Camellia sinensis cultivated in Turkey and effects on the in vitro inhibition of CYP2D6 enzyme.

Tea is a worldwide consumed herbal beverage and it was aimed in this study to reveal the major fractions of green and black tea in order to enlighten the in vitro inhibition potency on the well-known drug metabolizing enzyme CYP2D6 activity. Methylxanthine fractions were extracted from green and black tea and a yield of 0.265 g (1.06%) for 25 g of dried black tea and 0.302 g (1.2%) for 25 g of green tea was calculated. High-performance liquid chromatography analysis represented that the major components of the methylxanthine fractions were caffeine, theobromine, and theophylline. Methylxanthine content of black tea was 368.25 ± 4.6 µg/ml caffeine, 89.30 ± 2.3 µg/ml theobromine, and 3.40 ± 0.5 µg/ml theophylline, whereas that of green tea was 176.50 ± 3.7 µg/ml caffeine, 53.85 ± 1.4 µg/ml theobromine, and 2.06 ± 0.7 µg/ml theophylline. The results of concentration-dependent inhibition studies were 76% green tea, 75% black tea, and 55% caffeine at concentration of 10 mg/ml. The inhibition rates of green and black tea on CYP2D6 activity were 76% and 75%, respectively, where that of quinidine, the well-known inhibitor of CYP2D6, was 82%. Our results indicate that green and black tea is very likely to modify the CYP2D6 enzyme activity.

Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity.

The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty-seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3-hydroxymorphinan (3HM), were determined from a 2-hour post-dose plasma sample and cumulative 4-hour urine sample using liquid chromatography-mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P = .03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P = .04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P = .02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all-trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.

Luteolin Alleviates Oxidative Stress in Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke via Modulation of the TRPV1 and CYP2A13/NRF2 Signaling Pathways.

The current study aims to investigate the therapeutic potential of luteolin (Lut), a naturally occurring flavonoid found in various medicinal plants, for treating chronic obstructive pulmonary disease (COPD) through both in vitro and in vivo studies. The results demonstrated that Lut increased body weight, reduced lung tissue swelling and lung damage indices, mitigated systemic oxidative stress levels, and decreased alveolar fusion in cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD mice. Additionally, Lut was observed to downregulate the expression of the TRPV1 and CYP2A13 proteins while upregulating SIRT6 and NRF2 protein expression in CS + LPS-induced COPD mice and cigarette smoke extract (CSE)-treated A549 cells. The concentrations of total reactive oxygen species (ROS) and mitochondrial ROS in A549 cells induced by CSE significantly increased. Moreover, CSE caused a notable elevation of intracellular Ca2+ levels in A549 cells. Importantly, Lut exhibited inhibitory effects on the inward flow of Ca2+ and attenuated the overproduction of mitochondrial and intracellular ROS in A549 cells treated with CSE. In conclusion, Lut demonstrated a protective role in alleviating oxidative stress and inflammation in CS + LPS-induced COPD mice and CSE-treated A549 cells by regulating TRPV1/SIRT6 and CYP2A13/NRF2 signaling pathways.