α-Oxidation of 3-methyl-substituted fatty acids in rat liver

Huang, Shuigen; Veldhoven, Paul P. Van; Vanhoutte, Filip; Parmentier, G.; Eyssen, H.; Mannaerts, Guy P.

doi:10.1016/0003-9861(92)90565-e

Cited by 54 publications

(22 citation statements)

References 29 publications

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“…Unlabelled formyl-CoA (50 nmol in 7 ul) was added as a carrier to 750 ul of the filtrate (450 ul for 3-methyl[l- 14 C]palmitate as a substrate), 700 ul (400 ul) of which was injected onto a Nova-Pak Qg HPLC column (3.9 X 150 mm, 4 urn, 60 À).…”

Section: Analysis Of the Reaction Medium Formentioning

confidence: 99%

Production of formyl‐CoA during peroxisomal α‐oxidation of 3‐methyl‐branched fatty acids

et al. 1997

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a-Oxidation of 3-methyl-substituted fatty acids was studied in purified rat liver peroxisomes. The experiments revealed that formyl-CoA is formed during the a-oxidation process. The amount of formyl-CoA found constituted 2-5% of the amount of formate formed. Under the conditions used, no activation of exogenously added formate occurred in purified peroxisomes, whereas 95.5% of added synthetic formyl-CoA was converted to formate. These data indicate that during aoxidation first formyl-CoA is formed, which is then hydrolysed to formate.

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Section: Analysis Of the Reaction Medium Formentioning

confidence: 99%

Production of formyl‐CoA during peroxisomal α‐oxidation of 3‐methyl‐branched fatty acids

et al. 1997

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“…Starvation and fasting induced CYPs 2E1, 3A2, 2B and 4A, and reduced CYPs 2C11 and 1A2 in the metabolic activity of rat hepatic microsomes. [7][8][9][10]33) Starvation increased the microsomal a-and boxidation of fatty acids in rat hepatocytes, 35,36) and w-oxidation by CYP4A1 in the microsomes. 7) Elevation of CYP 2E1 seemed to result from increased lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

4'-Hydroxylation of Flurbiprofen by Rat Liver Microsomes in Fasting and Feeding Conditions

Shimizu

Matsushita

Matsumoto

et al. 2003

Biological & Pharmaceutical Bulletin

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Flurbiprofen (FP) is a nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class. Although it possesses a chiral center, both R-(Ϫ)-and S-(ϩ)-enantiomers may possess analgesic activity, and all FP-preparations to date are marketed as the racemate. The enantiomers exhibit differences in both the level of protein binding and metabolism.1) The former difference was observed using ultracentrifugation 2) but not using equilibrium dialysis. 3,4) The latter difference was observed in diastereomeric glucuronides, but the enantiomers were undiscernibly metabolized by oxidation via the cytochrome P450 system (CYP), followed by glucuronidation.1) The major oxidative metabolites were 4Ј-hydroxy and 3Ј,4Ј-dioxygenated metabolites (Fig. 1), 5) and it was known that 4Ј-hydroxy-flurbiprofen (4Ј-HOFP) was transformed from FP involving in CYP 2C9 and not CYPs 1A2, 2C8, 2E1, or 3A4 in human. 6) Very little is known of the metabolic capabilities by CYP isoforms in rat liver microsomes.Since drugs are sometimes administered to experimental animals after overnight fasting, it is necessary to know whether the metabolism of FP is changed after the fasting. Starvation and fasting change both the composition of cytochrome P450s and the metabolic activity of rat hepatic microsomes, inducing CYPs 2B1, 2E1, and 3A2, and reducing CYPs 1A2 and 2C11.7-10) Our study describes that 4Ј-hydroxylation of FP, being a primitive metabolism, was conducted by rat microsomal CYP2C11, but not CYP2E1 induced on fasting, and also provides a possibility that the CYP2E1 might contribute to further oxidation following the 4Ј-hydroxylation. MATERIALS AND METHODSChemicals Aniline, cimetidine, disulfiram, flurbiprofen, p-aminophenol, quinine, testosterone, and troleandomycin were purchased from Wako Pure Chemicals (Tokyo). Diclofenac, furafylline, glucose-6-phosphate and SKF-525A were from Sigma Chemical Co. Kanamycin was from Meiji Seika (Tokyo), and anti-rat CYP2C11 serum and anti-rat CYP2E1 serum were from Dai-ichi Pure Chemicals Co. (Tokyo). G-6-P-D, b-NADP, and b-NADPH were from Oriental Ferm. Co. (Tokyo).Treatment of Animals Male Wistar rats (250-300 g) were obtained from Charles River Laboratories, Inc. (Japan). The animals were housed in cages under controlled conditions of temperature and humidity, and were subjected to a 12-h light/dark cycle. The rats were fed Oriental laboratory diets for the feeding condition and were fasted for 24 h for the fasting condition. They had free access to water under the both conditions.Preparation of Rat Liver Microsomes The animals were killed by decapitation, and individual liver microsomes were prepared by a general method: The liver was homogenized with 0.25 M sucrose (9 vol.) to give a supernatant by centrifugation at 1000ϫg for 10 min and then 9000ϫg for 20 min, then the supernatant was centrifuged at 105000ϫg for 60 min to give a pellet. The microsomal pellet was suspended in 0.1 M potassium phosphate buffer (pH 7.4) and stored at Ϫ30°C until use.Microsomal Protein Assay Microsomal protein conc...

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“…Also, the report that phytanic acid oxidation is defective in patients with cytochrome c oxidase deficiency [34] indicates that mitochondria are involved in the production of radiolabelled CO 2 from [1-~4C]phytanic acid. A report that aoxidation of phytanic acid is mainly microsomal in rat liver [35] further adds to the confusion. In all of these studies, radiolabelled CO2 production from [1-~4C]phytanic acid was taken as evidence of c~-oxidation.…”

Section: Discussionmentioning

confidence: 99%

“…In all of these studies, radiolabelled CO2 production from [1-~4C]phytanic acid was taken as evidence of c~-oxidation. Furthermore, a-oxidation activities measured were very low [27][28][29][30][31][32][33][34][35]. Recent studies from our laboratory [36] provide evidence that formic acid is the major ~-oxidation product in human skin fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Substrate specificity of rat liver mitochondrial carnitine palmitoyl transferase I: evidence against α‐oxidation of phytanic acid in rat liver mitochondria

Singh

Poulos

1995

FEBS Letters

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The two branched chain fatty acids pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) and phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) were converted to coenzyme A thioesters by rat liver mitochondrial outer membranes. However, these branched chain fatty acids could not be converted to pristanoyl and phytanoyl carnitines, respectively, by mitochondrial outer membranes. As expected, the unbranched long chain fatty acids, stearic acid and palmitic acid, were rapidly converted to stearoyl and palmitoyl carnitines, respectively, by mitochondrial outer membranes. These observations indicate that the branched chain fatty acids could not be transported into mitochondria. The data presented strongly suggest that in rat liver, c~-oxidation of phytanic acid occurs in organelles other than mitochondria.demonstrated that CPTI activity is reversibly inhibited by malonyl-CoA. Recently, it has been shown that malonyl-CoA inhibits peroxisomal, microsomal and plasma membrane carnitine acyl transferases [8,10,13]. Therefore, in order to understand the role of CPTI in fatty acid oxidation, CPTI must be separated from other carnitine acyl transferases. In view of the difficulties in isolating CPTI in the active state, we decided to investigate CPTI activity in highly purified mitochondrial outer membranes from rat liver. We present evidence that branched chain fatty acids with ~-or fl-methyl groups are poor substrates for CPTI, suggesting that these branched chain fatty acids cannot be transported into mitochondria via the carnitine/ acylcarnitine transport system.

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α-Oxidation of 3-methyl-substituted fatty acids in rat liver

Cited by 54 publications

References 29 publications

Production of formyl‐CoA during peroxisomal α‐oxidation of 3‐methyl‐branched fatty acids

Production of formyl‐CoA during peroxisomal α‐oxidation of 3‐methyl‐branched fatty acids

4'-Hydroxylation of Flurbiprofen by Rat Liver Microsomes in Fasting and Feeding Conditions

Substrate specificity of rat liver mitochondrial carnitine palmitoyl transferase I: evidence against α‐oxidation of phytanic acid in rat liver mitochondria

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