Influence of some aliphatic alcohols on the metabolism of rat liver slices.
Ontology highlight
ABSTRACT:
SUBMITTER: Forsander OA
PROVIDER: S-EPMC1198278 | biostudies-other | 1967 Oct
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Menthofuran is a monoterpene present in mint plants that is oxidized by mammalian cytochrome P450 (CYP) to hepatotoxic metabolites. Evidence has been presented that p-cresol and other unusual oxidative products are metabolites of menthofuran in rats and that p-cresol may be responsible in part for the hepatotoxicity caused by menthofuran [ Madyastha, K. M. and Raj, C. P. (1992) Drug Metab. Dispos. 20, 295 - 301]. In the present study, several oxidative metabolites of menthofuran were characterized in rat and human liver microsomes and in rat liver slices exposed to cytotoxic concentrations of menthofuran. Metabolites that were identified were monohydroxylation products of the furanyl and cyclohexyl groups, mintlactones and hydroxymintlactones, a reactive γ-ketoenal, and a glutathione conjugate. A similar spectrum of metabolites was found in urine 24 h after the administration of hepatotoxic doses of menthofuran to rats. In no case was p-cresol (or any of the other reported unusual oxidative metabolites of menthofuran) detected above background concentrations that were well below concentrations of p-cresol that cause cytotoxicity in rat liver slices. Thus, the major metabolites responsible for the hepatotoxic effects of menthofuran appear to be a γ-ketoenal and/or epoxides formed by oxidation of the furan ring.
| S-EPMC2981629 | biostudies-literature
Project description:1. The influence of ethanol on the redox level of the redox pair lactate/pyruvate has been studied in experiments with rat-liver slices. 2. Ethanol had no effect on oxygen consumption but strongly depressed carbon dioxide formation. On the assumption that ethanol is oxidized to acetate in the liver slices, it could be calculated that most of the oxygen that disappeared was consumed in this reaction. 3. Addition of ethanol to the incubation medium increased the lactate/pyruvate ratio and when all the ethanol had been oxidized the redox value decreased to the normal again. Ethanol depressed the pyruvate concentration, whereas the lactate concentration was not much influenced. 4. Acetaldehyde in the concentrations present during ethanol oxidation did not influence the lactate/pyruvate ratio. Higher concentrations, however, increased the redox state. 5. Acetate in the concentrations present during ethanol oxidation in the experiments, and also in higher concentrations, did not influence the lactate/pyruvate ratio. 6. The mechanism by which ethanol influences the lactate/pyruvate ratio is discussed.
| S-EPMC1264821 | biostudies-other
Project description:All-trans-retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell-specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time-dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all-trans-retinoic acid (atRA), an active metabolite with antifibrogenic properties. Following chronic liver injury, vitamin A metabolic flux is perturbed, and HSC activation leads to diminished retinoid stores. WHAT QUESTION DID THIS STUDY ADDRESS? Do changes in the expression of vitamin A metabolizing enzymes explain changes in atRA concentrations and the regulation of fibrosis following acute liver injury? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The atRA concentrations are inversely correlated with profibrogenic gene expression, HSC activation, and collagen deposition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell-specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis.
| S-EPMC8212748 | biostudies-literature
Project description:Two important signaling pathways in liver fibrosis are the PDGF- and TGF? pathway and compounds inhibiting these pathways are currently developed as antifibrotic drugs. Testing antifibrotic drugs requires large numbers of animal experiments with high discomfort. Therefore, a method to study these drugs ex vivo was developed using precision-cut liver slices from fibrotic rat livers (fPCLS), representing an ex vivo model with a multicellular fibrotic environment. We characterized the fibrotic process in fPCLS from rat livers after 3 weeks of bile duct ligation (BDL) during incubation and tested compounds predominantly inhibiting the TGF? pathway (perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone) and PDGF pathway (imatinib, sorafenib and sunitinib). Gene expression of heat shock protein 47 (Hsp47), ? smooth muscle actin (?Sma) and pro-collagen 1A1 (Pcol1A1) and protein expression of collagens were determined. During 48 hours of incubation, the fibrosis process continued in control fPCLS as judged by the increased gene expression of the three fibrosis markers, and the protein expression of collagen 1, mature fibrillar collagen and total collagen. Most PDGF-inhibitors and TGF?-inhibitors significantly inhibited the increase in gene expression of Hsp47, ?Sma and Pcol1A1. Protein expression of collagen 1 was significantly reduced by all PDGF-inhibitors and TGF?-inhibitors, while total collagen was decreased by rosmarinic acid and tetrandrine only. However, fibrillar collagen expression was not changed by any of the drugs. In conclusion, rat fPCLS can be used as a functional ex vivo model of established liver fibrosis to test antifibrotic compounds inhibiting the PDGF- and TGF? signalling pathway.
| S-EPMC3995767 | biostudies-literature
Project description:The sensitive, selective, and practical detection of aliphatic alcohols is a continuing technical challenge with significant impact in public health research and environmental remediation efforts. Reported herein is the use of a ?-cyclodextrin derivative to promote proximity-induced interactions between aliphatic alcohol analytes and a brightly colored organic dye, which resulted in highly analyte-specific color changes that enabled accurate alcohol identification. Linear discriminant analysis of the color changes enabled 100% differentiation of the colorimetric signals obtained from methanol, ethanol, and isopropanol in combination with BODIPY and Rhodamine dyes. The resulting solution-state detection system has significant broad-based applicability because it uses only easily available materials to achieve such detection with moderate limits of detection obtained. Future research with this sensor system will focus on decreasing limits of detection as well as on optimizing the system for quantitative detection applications.
| S-EPMC6844157 | biostudies-literature
Project description:Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90?min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron-withdrawing substituents are transferred most efficiently, and unsymmetric iodonium salts give chemoselective arylations. The methodology has been applied to the formal synthesis of butoxycaine.
| S-EPMC4000167 | biostudies-literature
Project description:Unactivated ?-branched primary and secondary aliphatic alcohols have been successfully transformed into their corresponding alkyl chlorides in high yields upon treatment with a mixture of triphosgene and pyridine in dichloromethane at reflux. These mild chlorination conditions are high yielding, stereospecific, and well tolerated by numerous sensitive functionalities. Furthermore, no nuisance waste products are generated in the course of the reactions.
| S-EPMC4153350 | biostudies-literature
Project description:Alcohols and alkenes are the most abundant and commonly used organic building blocks in the large-scale chemical synthesis. Herein, this is the first time to report a novel and operationally simple coupling reaction of vinylarenes and aliphatic alcohols catalyzed by manganese in the presence of TBHP (tert-butyl hydroperoxide). This coupling reaction provides the oxyalkylated products of vinylarenes with good regioselectivity and accomplishes with the principles of step-economies. A possible reaction mechanism has also been proposed.
| S-EPMC4607950 | biostudies-literature
Project description:Probing the neural mechanisms that underlie each sensory system requires the presentation of perceptually appropriate stimulus concentrations. This is particularly relevant in the olfactory system as additional odorant receptors typically respond with increasing stimulus concentrations. Thus, perceptual measures of olfactory sensitivity provide an important guide for functional experiments. This study focuses on aliphatic alcohols because they are commonly used to survey neural activity in a variety of olfactory regions, probe the behavioral limits of odor discrimination, and assess odor-structure activity relationships in mice. However, despite their frequent use, a systematic study of the relative sensitivity of these odorants in mice is not available. Thus, we assayed the ability of C57BL/6J mice to detect a homologous series of primary aliphatic alcohols (1-propanol to 1-heptanol) using a head-fixed Go/No-Go operant conditioning assay combined with highly reproducible stimulus delivery. To aid in the accessibility of our data, we report the animal's threshold to each odorant according to the 1) ideal gas condition, 2) nonideal gas condition (factoring in the activity of the odorant in the solvent), and 3) the liquid dilution of the odorant in the olfactometer. Of the odorants tested, mice were most sensitive to 1-hexanol and least sensitive to 1-butanol. These updated measures of murine sensitivity will hopefully guide experimenters in choosing appropriate stimulus concentrations for experiments using these odorants.
| S-EPMC7750973 | biostudies-literature
Project description:The kinetics of oxidation of various alcohols by purified rat liver alcohol dehydrogenase (ADH) were compared with the kinetics of elimination of the alcohols in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. Primary alcohols (ethanol, 1-propanol, 1-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol) and diols (1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol) were eliminated in rats with zero-order kinetics at doses of 5-20 mmol/kg. Ethanol was eliminated most rapidly, at 7.9 mmol/kgh. Secondary alcohols (2-propanol-d7, 2-propanol, 2-butanol, 3-pentanol, cyclopentanol, cyclohexanol) were eliminated with first order kinetics at doses of 5-10 mmol/kg, and the corresponding ketones were formed and slowly eliminated with zero or first order kinetics. The rates of elimination of various alcohols were inhibited on average 73% (55% for 2-propanol to 90% for ethanol) by 1 mmol/kg of 4-methylpyrazole, a good inhibitor of ADH, indicating a major role for ADH in the metabolism of the alcohols. The Michaelis kinetic constants from in vitro studies (pH 7.3, 37 °C) with isolated rat liver enzyme were used to calculate the expected relative rates of metabolism in rats. The rates of elimination generally increased with increased activity of ADH, but a maximum rate of 6±1 mmol/kg h was observed for the best substrates, suggesting that ADH activity is not solely rate-limiting. Because secondary alcohols only require one NAD(+) for the conversion to ketones whereas primary alcohols require two equivalents of NAD(+) for oxidation to the carboxylic acids, it appears that the rate of oxidation of NADH to NAD(+) is not a major limiting factor for metabolism of these alcohols, but the rate-limiting factors are yet to be identified.
| S-EPMC4414724 | biostudies-literature