Hepatic Hydroxylation Research Articles

Formulation and Evaluation of Sublingual Tablets of Meclizine Hydrochloride

The aim of the present research is to formulate sublingual tablet of Meclizine Hydrochloride using direct compression method. Moreover the purpose of developing this dosage form is to provide rapid onset of action beneficial in managing conditions of nausea, vomiting and vertigo, and also overcome the problems of solubility of drug by inclusion complexes. The disease like nausea and vomiting required fast onset of action which is necessary for the fast pharmacological action. So, the sublingual route of administration were better way of medication and overcome the problems like dysphagia. The Meclizine hydrochloride is histamine H1 receptor antagonist with antiemetic and antivertigo properties. The oral bioavailability is low (25%), with low solubility (BCS class 2 drug), and metabolized by Hepatic CYP2D6 enzyme by the process of hepatic hydroxylation. Sublingual tablet of antiemetic drug meclizine hydrochloride will be prepared by direct compression method. The Solubility of sublingual tablets will be enhanced by Inclusion complexes. These are prepared by weighed amount of drug mixed with β-cyclodextrin in different dose ratios [1:1,1:2] was wetted with small drops of water to form kneaded like paste and triturated in mortar pestle for several hours resulting in evaporation of solvent. The inclusion complexes was collected and dried for 48 hours and pulverized using mortar and pestle and then sieved through mesh #60. Then properly mixed with other excipients in polybag for 1 hour. The powder like complex was used for further evaluation studies and to form sublingual tablets by direct compression method.

Bioanalytical LC-QTOF/MS Method for a N-phenylpiperazine Derivate (LQFM05): An Anxiolytic- and Antidepressant-like Prototype Drug Applied to Pharmacokinetic and Biodistribution Studies.

The LQFM05 is a prototype drug designed for treatment of psychiatric disorders, such as schizophrenia, exhibiting anxiolytic- and antidepressant-like (12 or 24 µmol/kg) effects in classical behavioral tests. In order to evaluate its pharmacokinetic properties, a liquid chromatography method coupled to a quadrupole time of flight mass spectrometry system (LC-QTOF/MS) was developed and fully validated for LQFM05 analysis in rat plasma and tissue samples (brain, heart, liver, and kidneys). Liquid-liquid extraction, solid phase extraction and protein precipitation were assessed as clean-up procedures for biological samples and analyte enrichment. Plasma and tissue samples underwent protein precipitation as a preliminary step, using acetonitrile. Linearity was fully demonstrated for the dynamic range (10.0 to 900.0 ng/mL), with r2 values higher than 0.99 (RSDslope ≤ 2%, Fcal < Ftab, Ccal < Ctab). Biodistribution studies in rats revealed high brain tissue concentrations (12.4 µg/g), suggesting elevated drug affinity to the main therapeutic target tissue, showing a blood partition coefficient of 1.9. Kidneys also showed great exposure and tissue affinity, suggesting a potential extrahepatic clearance. Likewise, all examined tissues exhibited satisfactory LQFMF05 distribution. The mass fragmentation spectrum indicated the presence of its main metabolite, LQFM235, yielded by high hepatic hydroxylation route, an equally bioactive derivative. Lastly, the developed LC-QTOF/MS method was shown to be sensitive (LOQ = 10 ng/mL), precise and accurate for LQFM05 determination in tissue homogenates and plasma samples.

Dietary supplementation of 25-hydroxycholecalciferolas an alternative tocholecalciferol in swine diets:A review.

25-hydroxycholecalciferol (25-OHD3 ) formed via hepatic hydroxylation from vitamin D, cholecalciferol, represents the precursor of the biologically active vitamin D hormone, 1,25-dihydroxyvitamin D. Due to a higher absorption rate and the omission of one hydroxylation, dietary supplementation of 25-OHD3 instead of vitamin D3 is considered to be more efficient as plasma concentrations of 25-OHD3 are increased more pronounced. The present review summarises studies investigating potential beneficial effects on mineral homeostasis, bone metabolism, health status and performance in sows, piglets and fattening pigs. Results are inconsistent. While most studies could not demonstrate any or only a slight impact of partial or total replacement of vitamin D3 by 25-OHD3 , some experiments indicated that 25-OHD3 might alter physiological processes when animals are challenged, for example,by a restricted mineral supply.

On solving an isotope dilution model for the partition of phenylalanine and tyrosine uptake by the liver of lactating dairy cows

AbstractAn isotope dilution model for partitioning phenylalanine and tyrosine uptake by the liver of the lactating dairy cow is constructed and solved in the steady state. An original ten-pool model is adopted and solved by cleaving it into two five-pool sub-models, one representing phenylalanine and the other tyrosine. If assumptions are made, model solution permits calculation of the rate of phenylalanine and tyrosine uptake from portal vein and hepatic arterial blood supply, hydroxylation, and synthesis and degradation of constitutive protein. The model requires the measurement of plasma flow rate through the liver in combination with amino acid concentrations and plateau isotopic enrichments in arterial and portal and hepatic vein plasma during a constant infusion of [1-13C]phenylalanine and [2,3,5,6-2H]tyrosine tracers. It also requires estimates of the rate of oxidation and protein export secretion. Analysis of measurement errors in experimental enrichments and infusion rates on model solutions indicated that accurate values of the intracellular and extracellular enrichments are central to minimising errors in the calculated flows. Solving the model by cleaving into two five-pool schemes rather than solving the ten-pool scheme directly is preferred as there appears to be less compounding of errors and the results consistently appear to be more biologically feasible. The model provides a means for assessing the impact of hepatic metabolism on amino acid availability to peripheral tissues such as the mammary gland.

Calcifediol for Use in Treatment of Respiratory Disease.

Calcifediol is the prohormone of the vitamin D endocrine system (VDES). It requires hydroxylation to move to 1,25(OH)2D3 or calcitriol, the active form that exerts its functions by activating the vitamin D receptor (VDR) that is expressed in many organs, including the lungs. Due to its rapid oral absorption and because it does not require first hepatic hydroxylation, it is a good option to replace the prevalent deficiency of vitamin D (25 hydroxyvitamin D; 25OHD), to which patients with respiratory pathologies are no strangers. Correcting 25OHD deficiency can decrease the risk of upper respiratory infections and thus improve asthma and COPD control. The same happens with other respiratory pathologies and, in particular, COVID-19. Calcifediol may be a good option for raising 25OHD serum levels quickly because the profile of inflammatory cytokines exhibited by patients with inflammatory respiratory diseases, such as asthma, COPD or COVID-19, can increase the degradation of the active metabolites of the VDES. The aim of this narrative revision is to report the current evidence on the role of calcifediol in main respiratory diseases. In conclusion, good 25OHD status may have beneficial effects on the clinical course of respiratory diseases, including COVID-19. This hypothesis should be confirmed in large, randomized trials. Otherwise, a rapid correction of 25(OH)D deficiency can be useful for patients with respiratory disease.

UK Nutrition Research Partnership 'Hot Topic' workshop: Vitamin D-A multi-disciplinary approach to (1) elucidate its role in human health and (2) develop strategies to improve vitamin D status in the UK population.

Vitamin D is truly unique-not a 'vital' amine in the true sense of the word, but rather a prohormone, which is produced in the skin during exposure to sunlight (UVB radiation at 290-315 nm) and which can also be obtained from food and from supplements. A high prevalence of low vitamin D status has been reported across the world in a wide range of population groups, and this includes communities living in low latitude areas despite the abundance of sunlight. It is accepted that vitamin D status is reflected by the level of the circulating metabolite 25-hydroxyvitamin D (25[OH]D), which is produced by hepatic hydroxylation of vitamin D, derived either from the skin from UV exposure or the gut from oral intake. Vitamin D has been associated with a wide range of health outcomes, but controversies remain as to their exact nature and extent and whether associations are in the causal pathway. In order to enable wider discussions on this nutrient, a 'Hot Topic' Vitamin D Workshop achieved funding from the UK Nutrition Research Partnership Medical Research Council call. The objectives of the workshop were (1) to elucidate the role of vitamin D in human health and (2) develop strategies to improve vitamin D status in the UK population. This paper provides a detailed resume of the discussions of the workshop; of the presentations and concomitant Q&As; and of identified areas for future research.

Differential effects of vitamin D3 vs vitamin D2 on cellular uptake, tissue distribution and activation of vitamin D in mice and cells

To combat vitamin D deficiency, vitamin D3 and vitamin D2 are commonly used as a supplement or to fortify food sources. Human data show that the response of 25-hydroxyvitamin D (25(OH)D) to supplementation with vitamin D3 is higher than to vitamin D2. To elucidate the metabolic route of both vitamers, we conducted a study with vitamin D-depleted mice, which were allotted into three groups (n = 12) and received equal doses of either deuterated vitamin D3, deuterated vitamin D2 or both for 4 weeks. To further investigate the hepatic uptake and hydroxylation of both D-vitamers to 25(OH)D, we conducted cell culture experiments with murine and human hepatoma cells (Hepa1-6 and HepG2). The vitamin D metabolite concentrations in serum, tissues and cells were analyzed by LC-MS/MS or ELISA.In mice, vitamin D2 resulted in lower serum and tissue concentrations of vitamin D (P < 0.001) than vitamin D3, while the group which received both D-vitamers showed values in between. Interestingly, vitamin D2 fed mice had 1.9-times and 2.9-times higher serum concentrations of total and free 25(OH)D (P < 0.001) than mice fed vitamin D3, while the concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) was 1.8-times lower (P < 0.001). The gene and protein expression of enzymes, involved in the hydroxylation and renal uptake of vitamin D remained largely unaffected by the D-vitamer. In contrast to the mice data, hepatoma cells preferred vitamin D3 for 25-hydroxylation over vitamin D2 (P < 0.001). In general, the formation of 25(OH)D was much more pronounced in human than in murine hepatoma cells (P < 0.001).To conclude, in contrast to humans, vitamin D2 was more efficient in increasing 25(OH)D than vitamin D3 in mice, although this difference was not caused by a preferential hydroxylation of vitamin D2 in the liver. The metabolic routes of D3 and D2 in mice differ, showing lower circulating 1,25(OH)2D and tissue vitamin D concentrations in D2- than in D3-fed mice.

Intake of ergosterol increases the vitamin D concentrations in serum and liver of mice

Factors that can modify the bioavailability of orally administered vitamin D are not yet widely known. Ergosterol is a common fungal sterol found in food which has a chemical structure comparable to that of vitamin D. This study aimed to investigate the effect of ergosterol on vitamin D metabolism. Therefore, 36 male wild type-mice were randomly subdivided into three groups (n = 12) and received a diet containing 25 μg vitamin D3 and either 0 mg (control), 2 mg or 7 mg ergosterol per kg diet for 6 weeks. To elucidate the impact of ergosterol on hepatic hydroxylation of vitamin D, human hepatoma cells (HepG2) were treated with different concentrations of ergosterol. Concentrations of vitamin D3 and 25-hydroxyvitamin D3 (25(OH)D3) in cells, livers and kidneys of mice and additionally 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) in serum were quantified by LC-MS/MS. The concentration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in serum was analyzed by commercially-available enzyme immuno assay. The concentrations of cholesterol and triglycerides were analyzed in livers of mice by photometric assays.Analyses revealed that mice receiving 7 mg/kg ergosterol with their diet had 1.3-, 1.7- and 1.5-times higher concentrations of vitamin D3 in serum, liver and kidney, respectively, than control mice (P < 0.05), whereas no significant effects were observed in mice fed 2 mg/kg ergosterol. The hydroxylation of vitamin D remained unaffected by dietary ergosterol, since the concentration of 25-hydroxyvitamin D3 in serum and tissues and the concentrations of 1,25(OH)2D3 and 24,25(OH)2D3 in serum were not different between the three groups of mice. The lipid concentrations in liver were also not affected by dietary ergosterol. Data from the cell culture studies showed that ergosterol did not influence the conversion of vitamin D3 to 25(OH)D3. To conclude, ergosterol appears to be a modulator of vitamin D3 concentrations in the body of mice, without modulating the hydroxylation of vitamin D3 in liver.

LC-MSMS characterisations of scymnol and oxoscymnol biotransformations in incubation mixtures of rat liver microsomes

The bile alcohol 5β-scymnol ([24R]-(+)-5β-cholestan-3α,7α,12α,24,26,27-hexol) is a therapeutic nutraceutical derived from marine sources, however very little is known about its potential for biotransformation as a xenobiotic in higher vertebrates. In this study, biotransformation products of scymnol catalysed by liver microsomes isolated from normal and streptozotocin (STZ)-treated male Wistar rats were characterised by liquid chromatography-tandem mass spectroscopy (LC-MSMS). In order of increasing polarity relative to the reversed phase sorbent, structural assignments were made for four biotransformation products, namely 3-oxoscymnol (5β-cholestan-3-one-7α,12α,24,26,27-pentol); 7-oxoscymnol (5β-cholestan-7-one-3α,12α,24,26,27-pentol); 3β-scymnol (5β-cholestan-3β,7α,12α,24,26,27-hexol) and 6β-hydroxyscymnol (5β-cholestan-3α,6β,7α,12α,24,26,27-heptol). In addition, a total of eight biotransformation products were characterised from microsomal incubations of crude oxoscymnol compounds, namely 7β-scymnol; 3,12-dioxoscymnol; 3,7-dioxoscymnol; 7,12-dioxoscymnol; 12-oxo-3β-scymnol; 7-oxo-3β-scymnol; 6β-hydroxy-12-oxoscymnol and 6β-hydroxy-7-oxoscymnol. Collectively, the results indicate hepatic enzyme-catalysed hydroxylation, dehydrogenation and epimerisation reactions on the steroid nucleus of scymnol, and provide an insight into biotransformation pathways for scymnol use as a therapeutic nutraceutical in higher vertebrates.

Evolving Role of Vitamin D in Immune-Mediated Disease and Its Implications in Autoimmune Hepatitis.

Vitamin D has immunomodulatory, anti-inflammatory, antioxidant, and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease. The goals of this review are todescribe the nature of these expanded roles, examine the implications of vitamin D deficiency in autoimmune hepatitis, and identify opportunities for future investigation. Abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses. Macrophages and dendritic cells can produce 1,25-dihydroxyvitamin D within the microenvironment. This active form of vitamin D can inhibit immune cell proliferation, promote an anti-inflammatory cytokine profile, expand regulatory T cells, enhance glucocorticoid actions, increase glutathione production, and inhibit hepatic stellate cells. Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases, and it has been associated with histological severity, advanced hepatic fibrosis, and non-response to conventional glucocorticoid therapy in autoimmune hepatitis. Vitamin D analogues with high potency, low calcemic effects, and independence from hepatic hydroxylation are possible interventions. In conclusion, vitamin D has properties that could ameliorate immune-mediated disease, and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases, including autoimmune hepatitis. Loss of vitamin D-dependent homeostatic mechanisms may promote disease progression. Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis.

Is vitamin D3 bad for the kidney?

Active vitamin D3 {1,25-dihydroxyvitamin D3 [1,25(OH)2D3], calcitriol} is a hormone best known for its role in modulating mineral balance. Its synthesis involves several steps, including a hepatic hydroxylation to calcidiol {25-hydroxyvitamin D [25(OH)D3]}, requiring the cytochrome P450 enzyme CYP2R1, and final activation in the kidney by CYP27B1, mostly expressed in proximal tubules. Also, the degradation of calcitriol and calcidiol is performed by CYP24A1 in the proximal tubule [1]. Importantly, only 1,25(OH)2D3 exerts significant biological activity, all other forms of vitamin D3 (i.e. intermediate metabolites of synthesis and degradation) are thought to have minimal or no biologic activity [1, 2]. As expected for a hormone that has many functions in controlling mineral homeostasis, the synthesis and degradation of calcitriol is tightly regulated by many calci- and phosphatotropic factors, including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), calcium and phosphate. In addition, immune cytokines modulate calcitriol levels...

Study the effect of curcumin on hepatic DNA damage in an experimental model of hepatic fibrosis

Background/aim: Curcumin, a member of the ginger family of species, has long been used to treat cases of hepatic dysfunction. Herein, we investigated the hepatoprotective and the anti-fibrotic activity of curcumin against carbon tetra chloride (CCL4)-induced hepatic damage. Material & methods: A total of 40 Male Wister Albino rats (200-225 g) were divided into 4 groups 10 per each. Group 1 (G1, normal control) was injected with the vehicle, olive oil, (0.1 ml/Kg body weight, i.p.) twice weekly. Group 2 was intragastrically administered curcumin (200 mg/Kg). Group 3 (CCL4) received CCL4 (0.1 ml/Kg, i.p.) twice weekly. Group 4 (CCL4 + curcumin) received both curcumin and CCL4. All treatments were given for 6 weeks. Results: Administration of CCL4 resulted in a significant elevation in the serum levels of ALT, AST, and the hepatic TBARS, ROS and hydroxyl proline and a significant decrease in the activities of hepatic GSH, CAT and SOD along with increased DNA damage and distorted histological structure of liver with obvious fibrosis. Administration of curcumin alleviated all these distorted parameters In conclusion, curcumin administration ameliorated CCL4- induced liver damage and reduced the hepatic fibrosis.

Investigation of hepatic warfarin metabolism activity in rodenticide-resistant black rats (Rattus rattus) in Tokyo by in situ liver perfusion

Anti-blood coagulation rodenticides, such as warfarin, have been used all over the world. They inhibit vitamin K epoxide reductase (VKOR), which is necessary for producing several blood clotting factors. This inhibition by rodenticides results in lethal hemorrhage in rodents. However, heavy usage of these agents has led to the appearance of rodenticide-resistant rats. There are two major mechanisms underlying this resistance, i.e., mutation of the target enzyme of warfarin, VKOR, and enhanced metabolism of warfarin. However, there have been few studies regarding the hepatic metabolism of warfarin, which should be related to resistance. To investigate warfarin metabolism in resistant rats, in situ liver perfusion of warfarin was performed with resistant black rats (Rattus rattus) from Tokyo, Japan. Liver perfusion is an in situ methodology that can reveal hepatic function specifically with natural composition of the liver. The results indicated enhanced hepatic warfarin hydroxylation activity compared with sensitive black rats. On the other hand, in an in vitro microsomal warfarin metabolism assay to investigate kinetic parameters of cytochrome P450, which plays a major role in warfarin hydroxylation, the Vmax of resistant rats was slightly but significantly higher compared to the results obtained in the in situ study. These results indicated that another factor like electron donators may also contribute to the enhanced metabolism in addition to high expression of cytochrome P450.

Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism.

Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH4). Physiologically, phenylalanine availability is governed by nutrient intake, whereas liver BH4 is kept at constant level. In phenylketonuria, PAH deficiency leads to elevated blood phenylalanine and is often caused by PAH protein misfolding with loss of function. Here, we report secondary hepatic BH4 deficiency in Pah-deficient mice. Alterations in de novo synthesis and turnover of BH4 were ruled out as molecular causes. We demonstrate that kinetically instable and aggregation-prone variant Pah proteins trap BH4, shifting the pool of free BH4 towards bound BH4. Interference of PAH protein misfolding with metabolite-based control of l-phenylalanine turnover suggests a mechanistic link between perturbation of protein homeostasis and disturbed regulation of metabolic pathways.

Biochemical Evidence for the Antitumor Potential of Garcinia mangostana Linn. On Diethylnitrosamine-Induced Hepatic Carcinoma.

Background:Garcinia mangostana is extensively used in most of the Indian herbal pharmaceuticals and nutraceuticals.Objective:The objective of this study was to elucidate the underlying biochemical protective mechanism of G. Mangostana Linn. fruit extract (GME) in deterioration of diethylnitrosamine (DEN)-induced hepatic carcinoma (HCC) in rats.Materials and Methods:The cancer was induced using DEN to the experimental rats and treated with GME (200, 400, and 600 mg/kg) to find its anticancer property. The cancer biomarkers such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), hepatic hydroxyl proline, total tissue protein, and tumor necrosis factor-alpha levels were measured using ELISA. The vascular endothelial growth factor expressions were also seen in liver tissues using immunohistochemistry.Results:In addition, there was a significant increase in serum AFP, CEA, hepatic hydroxylproline, and total tissue protein levels in HCC group versus the negative control group. In contrast, the groups with HCC subjected to either high or low dose of GME elicited significant reduction of AFP, CEA, hepatic hydroxylproline, and increase in total protein in serum compared to the untreated HCC rats. Interestingly, treatment with GME elicited marked improvement in the liver histological feature and downregulation of tumor necrosis factor-alpha levels in HCC groups. GME extract may have chemopreventive benefits by reducing the tumor promoting growth factor levels in HCC-induced group.Conclusion:To sum up, all findings on curative groups had proved clearly that the GME has anticarcinogenic effect on the development of liver cancer induced by DEN in rats.SUMMARY Garcinia mangostana Linn. (GME) may have chemopreventive property by reducing the tumor promoting growth factor and tumor necrosis factor-alpha levels in diethylnitrosamine (DEN)-induced hepatic cancerThe suppression in the levels of cancer biomarkers by GME due to the presence of anticancer phytoconstituentsThe histological studies proved the effective dose of GME against DEN-induced experimental hepatic cancer. Abbreviations used: TNF-α: Tumor necrosis factor-alpha, PBS: Phosphate buffered saline, ROS: Reactive oxygen species, DNA: Deoxyribonucleic acid, GSH: Glutathione, VEGF: Vascular endothelial growth factor.

The hypophagic response to heat stress is not mediated by GPR109A or peripheral β-OH butyrate

Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating β-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal β-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of β-OH butyrate in heat stress hypophagia in mice. We found that niacin, a β-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal β-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to β-OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of β-OH butyrate at the central nervous system: β-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic β-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis.

Study on Synthesis of a Series of Hydroxyl Functional Cholesterylated Hepatic Targeting Liposome Ligands

A series of hepatic hydroxyl functional cholesterylated hepatic targeting liposome ligands T1-T6 were synthesized. Cholesterol as starting material, after esterification with p-toluenesulfonyl chloride to get cholesterol tosylate, then etherification with oligo ethylene ethanol (n=1-3) to get hydroxyl functional cholesterylated compounds T1-T3, T1-T3 were elongated by reaction with protected diethylene glycol and deprotected in acid condition to get T4-T6 . The target compounds affords cholesterylated hepatic targeting liposome ligands.

Three measurable and modifiable enteric microbial biotransformations relevant to cancer prevention and treatment.

Interdisciplinary scientific evaluation of the human microbiota has identified three enteric microbial biotransformations of particular relevance for human health and well-being, especially cancer. Two biotransformations are counterproductive; one is productive. First, selective bacteria can reverse beneficial hepatic hydroxylation to produce toxic secondary bile acids, especially deoxycholic acid. Second, numerous bacterial species can reverse hepatic detoxification—in a sense, retoxify hormones and xeonobiotics—by deglucuronidation. Third, numerous enteric bacteria can effect a very positive biotransformation through the production of butyrate, a small chain fatty acid with anti-cancer activity. Each biotransformation is addressed in sequence for its relevance in representative gastrointestinal and extra-intestinal cancers. This is not a complete review of their connection with every type of cancer. The intent is to introduce the reader to clinically relevant microbial biochemistry plus the emerging evidence that links these to both carcinogenesis and treatment. Included is the evidence base to guide counseling for potentially helpful dietary adjustments.

Role of hepatic cytochrome P450 oxidoreductase in bone development (921.1)

Cytochrome P450 oxidoreductase (POR) is the only known electron donor for Cytochromes P450 (CYPs), heme oxygenase (HO), and dehydrocholesterol reductase in the endoplasmic reticulum (ER). Hepatic CYPs are essential for the metabolism of cholesterol, steroids, sex hormones, and xenobiotics, such as drugs and toxins. Thus, alterations in POR activity will have multiple effects on the physiological activity of multitudinous metabolites. Human mutations in POR have been reported and present as altered steroidogenic profiles, severe craniofacial and bone defects resembling Antley‐Bixler syndrome (ABS). Liver‐specific POR null (LCN) mice were examined to study endo‐ and xeno‐biotic metabolism. Surprisingly, previous studies demonstrated only minor changes in plasma and intestinal lipid content of LCN mice, suggesting that lipid homeostasis is maintained despite significant hepatic steatosis. Here, we show for the first time that the deletion of POR from the liver leads to decreased bone volume in both cortical and trabecular compartments, as measured by micro computed tomography analysis, but no notable skull defects. In bone‐specific POR null mice, however, we have previously observed defects in skull morphology and trabecular bone density. This difference suggests that the action of hepatic CYP‐derived circulating metabolites is critical for normal bone development and is distinct from bone‐ specific CYP activity. There are several potentially important metabolites that could affect bone homeostasis and require hepatic CYP hydroxylation such as vitamin D, retinoic acid and steroid hormones. These data highlight the importance of both systemic and local POR activity in healthy bone development.Grant Funding Source: Supported by NIH grant GM081568 to BSSM and SPP

Hepatic bile acid metabolism and expression of cytochrome P450 and related enzymes are altered in Bsep −/− mice

The bile salt export pump (BSEP/Bsep; gene symbol ABCB11/Abcb11) translocates bile salts across the hepatocyte canalicular membrane into bile in humans and mice. In humans, mutations in the ABCB11 gene cause a severe childhood liver disease known as progressive familial intrahepatic cholestasis type 2. Targeted inactivation of mouse Bsep produces milder persistent cholestasis due to detoxification of bile acids through hydroxylation and alternative transport pathways. The purpose of the present study was to determine whether functional expression of hepatic cytochrome P450 (CYP) and microsomal epoxide hydrolase (mEH) is altered by Bsep inactivation in mice and whether bile acids regulate CYP and mEH expression in Bsep (-/-) mice. CYP expression was determined by measuring protein levels of Cyp2b, Cyp2c and Cyp3a enzymes and CYP-mediated activities including lithocholic acid hydroxylation, testosterone hydroxylation and alkoxyresorufin O-dealkylation in hepatic microsomes prepared from female and male Bsep (-/-) mice fed a normal or cholic acid (CA)-enriched diet. The results indicated that hepatic lithocholic acid hydroxylation was catalyzed by Cyp3a/Cyp3a11 enzymes in Bsep (-/-) mice and that 3-ketocholanoic acid and murideoxycholic acid were major metabolites. CA feeding of Bsep (-/-) mice increased hepatic Cyp3a11 protein levels and Cyp3a11-mediated testosterone 2β-, 6β-, and 15β-hydroxylation activities, increased Cyp2b10 protein levels and Cyp2b10-mediated benzyloxyresorufin O-debenzylation activity, and elevated Cyp2c29 and mEH protein levels. We propose that bile acids upregulate expression of hepatic Cyp3a11, Cyp2b10, Cyp2c29 and mEH in Bsep (-/-) mice and that Cyp3a11 and multidrug resistance-1 P-glycoproteins (Mdr1a/1b) are vital components of two distinct pathways utilized by mouse hepatocytes to expel bile acids.