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PubMed1992

7 alpha-hydroxylation of 26-hydroxycholesterol, 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid by cytochrome P-450 in pig liver microsomes.

Pig liver microsomes were found to catalyze the 7 alpha-hydroxylation of several potential bile acid precursors besides cholesterol. 26-Hydroxycholesterol, 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid were all efficiently converted into the 7 alpha-hydroxylated products. Two cytochrome P-450 fractions showing 7 alpha-hydroxylase activity could be isolated. One fraction catalyzed 7 alpha-hydroxylation of 26-hydroxycholesterol, 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid but was inactive towards cholesterol. The other fraction catalyzed 7 alpha-hydroxylation of cholesterol in addition to the other substrates. 26-Hydroxycholesterol in equimolar concentration did not inhibit the cholesterol 7 alpha-hydroxylase activity of this fraction. It is concluded that liver microsomes contain a cytochrome P-450 catalyzing 7 alpha-hydroxylation of 26-hydroxycholesterol, 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid. The results indicate that this cytochrome P-450 is different from that catalyzing 7 alpha-hydroxylation of cholesterol.

Animals↗

PubMed1990

Studies on the biosynthesis of iturin, an antibiotic of Bacillus subtilis, and a lipopeptide containing beta-hydroxy fatty acids.

The biosynthesis of iturin, an antibiotic containing a beta-amino fatty acid, was studied by incubating Bacillus subtilis in the presence of various 14C-labelled precursors. Sodium acetate or palmitic acid were incorporated into the beta-amino acids of iturin. Among the alpha-amino acids (asparagine, glutamine, serine, proline and tyrosine) in the peptidic part of iturin, asparagine appears to be the best precursor. In the presence of sodium [14C]acetate or [14C]asparagine, there was a synthesis of radioactive compound (compound X) before the synthesis of radioactive iturin. Compound X contained asparagine and/or aspartic acid, glutamine and/or glutamic acid and beta-hydroxy fatty acids.

Acetates↗

PubMed1989

Synthesis of hydroxy fatty acids from linoleic acid by human blood platelets.

The metabolism of linoleic acid by washed human platelets was investigated. [1.14C] linoleic acid was converted to [1.14C] hydroxy octadecadienoic acids (HODEs) at about the same rate with which [1.14C] 12-HETE was produced from [1.14C] arachidonic acid. The total radioactivity in HODEs was distributed among two isomers: 13-HODE (85%) and 9-HODE (15%) as defined by CG-MS. The production of HODEs by intact washed platelets was inhibited by indomethacin (IC50:5 x 10(-7) M) which suggest that hydroxy fatty acids were produced by PGH-synthase. By contrast, the production of HODEs by platelet cytosolic fractions was not modified under indomethacin treatment but completely abolished by NDGA (10(-3) M) and inhibited by the platelet lipoxygenase inhibitors 15-HETE (2.10(-5) M) and baicalein (10(-5) M). Platelets thus contain two different active systems which may convert linoleic acid to hydroxy fatty acids. Since these compounds remained essentially associated with the platelets, their presence may significantly participate in the mechanisms of platelet activation.

Arachidonate 15-Lipoxygenase↗

PubMed1986

Excretion of dicarboxylic and omega-1 hydroxy fatty acids by low birth weight infants fed with medium-chain triglycerides.

The effects of feeding a commercial formula containing increased amounts of medium-chain fatty acids on the urinary excretions of C6-C10 moncarboxylic, dicarboxylic, and omega-1 hydroxy acids were studied in 13 growing preterm infants of mean birth weight 1.42 kg in a randomized double-blind cross-over clinical trial. Infants were allocated to two sequential feeding regimes of 5 days each, during the last 3 days of which urine was collected and analysed by gas-chromatography mass spectrometry. The two feeding regimes consisted of high energy and protein-containing formulas specially designed for growing low birth weight infants. In one diet the triglyceride component consisted of 46% medium-chain (C8-C10) and 54% long-chain fatty acid residues: in the other it consisted of 4% medium-chain and 96% fatty acid residues. The infants were randomized so that six infants were fed first with the medium-chain predominant formula and seven were fed first with the long-chain predominant formula. There were significant differences in the urinary excretions of octanoate, sebacate, suberate, adipate, 7-hydroxyoctanoate, and 5-hydroxyhexanoate; these substances appearing in much greater quantities in the urine during the period in which medium-chain triglycerides were predominant in the formula. The significance of this organic aciduria, which accounted for 0.7% of the dietary intake of medium-chain triglycerides, remains to be established.

Dicarboxylic Acids↗

PubMed1983

On the biologic origin of C6-C10-dicarboxylic and C6-C10-omega-1-hydroxy monocarboxylic acids in human and rat with acyl-CoA dehydrogenation deficiencies: in vitro studies on the omega- and omega-1-oxidation of medium-chain (C6-C12) fatty acids in human and rat liver.

C6-C10-dicarboxylic acid C6-C10-omega-1-hydroxy monocarboxylic acids were measured in postmitochondrial (10,000 g) fractions of rat liver after incubation with hexanoic, octanoic, and decanoic acids. In livers both from fed and starved rats, the proportion of decanoic acid converted to sebacic acid was high (approximately 25%) with only minor accumulation of the intermediate 10-hydroxy decanoic acid (1-2%). The conversion of octanoic and hexanoic acids to suberic and adipic acids, respectively, was low (less than 1%). The intermediate 8-hydroxy octanoic and 6-hydroxy hexanoic acids were also accumulated in very small amounts (less than 1%). It was concluded that cytochrome-P-450-mediated omega-hydroxylation was of decisive importance for the production rate of the dicarboxylic acids. Analysis of kinetic parameters of human and rat liver microsomal omega- and omega-1-hydroxylation of hexanoic, octanoic, decanoic, and dodecanoic acids gave the following results: in rats, the apparent Km values for the omega-hydroxylation for dodecanoic and decanoic acids are low, ie., 171 and 3.1 mumole/liter, respectively, whereas they are high for octanoic and hexanoic acids (8211 and 8822 mumole/liter, respectively). In two different humans, the corresponding Km values for dodecanoic, decanoic, octanoic, and hexanoic acids are 3.6-186, 522-247, 4861-3892, and 6825-10400 mumole/liter, respectively. Based on these results, it is argued that adipic and suberic acids found in urine from rats and humans with acyl-CoA dehydrogenation deficiencies are not biosynthesized by direct omega-oxidation of hexanoic and octanoic acids, but most probably by means of beta-oxidation of sebacic and dodecanedioic acids, produced by direct omega-oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipates↗

PubMed1996

Increase in hydroxy fatty acids in human low density lipoproteins with age.

The content of hydroxy fatty acids in low density lipoprotein (LDL) of healthy volunteers aged between 22 and 87 years without any signs of atherosclerosis or other age-dependent diseases was investigated. The level of hydroxy fatty acids obtained from LDL increases during life time: clinically healthy persons between 56 and 66 years showed a 3- to 4-fold increase compared to young volunteers. This level increased in samples of probands aged 68 to 74 years compared to samples of young people for a factor of 10-20 and in samples of probands aged 78 to 87 years for a factor of 30-40. These hydroxy acids--generated mainly from hydroperoxy acids on linoleic acid and only partly from arachidonic acid--are obviously parameters of the LDL oxidation stage. About 90% of the total amount of hydroxy fatty acid were free fatty acids. The distribution patterns of the monohydroxy derivatives of linoleic and arachidonic acid indicate that they originate mainly from autocatalytic processes. The individual level of hydroxy acids is probably an indicator of the biological age.

Adult↗

PubMed1991

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytochrome P450IIB1 in a reconstituted system.

Several previous studies have suggested that cytochrome P450IIB1 is involved in the bioactivation of the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in rats as well as in mouse lung microsomes. The present investigation was undertaken to study the metabolism of NNK by purified cytochrome P450IIB1 in a reconstituted system. The metabolites 4-hydroxy-4-(3-pyridyl) butyric acid (hydroxy acid), 4-oxo-4-(3-pyridyl) butyric acid (keto acid), 4-oxo-4-(3-pyridyl) butanol (keto aldehyde), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide) and 4-oxo-4-(3-pyridyl)-1-butanol (keto alcohol) were quantitated by HPLC. The results showed that, in addition to alpha-hydroxylations, cytochrome P450IIB1 also catalyzed the formation of NNK-N-oxide efficiently, and to a certain extent, the conversion of NNK primary hydroxylation metabolites (keto aldehyde and keto alcohol) to secondary metabolites (keto acid and hydroxy acid). Cytochrome b5 at a ratio of 1:1 or 2:1 to P450IIB1 had no significant effect on the metabolic activities and profiles of NNK. The apparent Km values for the formation of keto aldehyde, NNK-N-oxide and keto alcohol were respectively 191.2, 131.4 and 318.0 microM with corresponding apparent Vmax values of 89.7, 295.5 and 333.3 pmol/min/nmol P450, indicating that hydroxylation at the alpha-methyl position is preferred over the alpha-methylene position. Measurement of formaldehyde, a product derived from the alpha-methyl hydroxylation, was developed as a convenient method to study NNK metabolism. Thiourea activated cytochrome P450IIB1-catalyzed NNK metabolism significantly. Phenethyl isothiocyanate, an inhibitor of NNK-induced lung carcinogenesis, inhibited P450IIB1-catalyzed NNK demethylation in a concentration-dependent manner. This work demonstrates that purified P450IIB1 can catalyze the conversion of NNK to most of its oxidative metabolites.

Animals↗

PubMed1985

Metabolism of 7,10,13,16-docosatetraenoic acid to dihomo-thromboxane, 14-hydroxy-7,10,12-nonadecatrienoic acid and hydroxy fatty acids by human platelets.

Human platelets metabolize 7,10,13,16-docosatetraenoic acid (22:4(n - 6)) into dihomo-thromboxane B2 and 14-hydroxy-7,10,12-nonadecatrienoic acid at about twenty percent of the rate they convert arachidonic acid to thromboxane B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid. 14-Hydroxy-7,10,12,16-docosatetraenoic was the major metabolite produce via the lipoxygenase pathway. Several other hydroxy acids were also produced in small amounts via an indomethacin-insensitive pathway. Incubation of 20 microM arachidonic acid with various levels of 22:4(n - 6) resulted in a dose-dependent inhibition of both thromboxane B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid production. Conversely, 12-hydroxy-5,8,10,14-eicosatetraenoic acid synthesis was stimulated because of substrate shunting to the lipoxygenase pathway. These results show that 22:4(n - 6) may modify platelet function both by serving as a precursor for a 22-carbon thromboxane and by suppressing the synthesis of thromboxane A2 from arachidonic acid. In addition, our results suggest that simultaneous release of 22:4(n - 6) and arachidonic acid from platelet phospholipids will result in an elevation of both 12-hydroxy-5,8,10,14-eicosatetraenoic acid levels as well as simultaneous synthesis of 14-hydroxy-7,10,12,16-docosatetraenoic acid.

Blood Platelets↗

PubMed1987

Biosynthesis of 3-hydroxy fatty acids, the pheromone components of female mallard ducks, by cell-free preparations from the uropygial gland.

Diesters of 3-hydroxy C8, C10, and C12 acids, the female mallard duck pheromones, were found as the major products of the uropygial glands only during the breeding season. The 3-hydroxy acids were identified by mass spectrometry of the trimethylsilyl ethers of the methyl esters and of the diols derived from LiAlH4 reduction of the hydroxy acids. A cell-free extract from the gland catalyzed conversion of dodecanoic acid to 3-hydroxydodecanoic acid which was identified by radio thin-layer and radio gas chromatographic analysis of the enzymic products as methyl-3-acetoxydodecanoate and as diacetate of the diol generated by LiAlH4 reduction of the enzymic product. The enzymic introduction of the hydroxyl group at C-3 was catalyzed mainly by a 50,000g pellet prepared from a 1000g supernatant obtained from the cell-free extract. This reaction required ATP, CoA, and O2, and the CoA ester of the acid was more efficiently converted than the free acid to the 3-hydroxy acid. KCN at 1 mM and 50% CO did not inhibit the reaction. 3H from 3H2O was incorporated into 3-hydroxydodecanoic acid during the enzymic synthesis of this acid from dodecanoic acid. Mass spectrometry of the 3-hydroxy acid generated by the particulate fraction in the presence of H2 18O showed that 18O was incorporated as expected from hydration of a delta 2 double bond. From the above results it is tentatively concluded that peroxisomal acyl-CoA oxidase converts the acyl-CoA to the 2-enoyl-CoA which is hydrated to generate the 3-hydroxy acid.

Adenosine Triphosphate↗

PubMed1993

Bis-allylic hydroxylation of polyunsaturated fatty acids by hepatic monooxygenases and its relation to the enzymatic and nonenzymatic formation of conjugated hydroxy fatty acids.

[14C]Linoleic acid was incubated with phenobarbital-induced rat liver microsomes and formation of cis-trans-conjugated hydroxy fatty acids was investigated. 13-Hydroxy-9Z,11E-octadecadienoic acid (13-HODE), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and three novel metabolites were identified, viz. 11-hydroxy-9Z,12Z-octadecadienoic acid (11-HODE), 8-HODE, and 14-HODE. 11-HODE (59% R), the main product, was unstable and converted to 9(R, S)-HODE and 13(R, S)-HODE in acidic media. All metabolites contained oxygen from O2. Experiments under oxygen-18 gas showed that 13-HODE and 9-HODE contained equal or less amounts of oxygen-18 than the other metabolites. In the former case, 9-HODE and 13-HODE were formed with stereo-selectivity (80-82% R). [11S-2H]Linoleic acid was metabolized to 13R-HODE with loss of deuterium (24% 2H) and to 9R-HODE with deuterium retention (95% 2H), while [11R-2H]linoleic acid was metabolized to 13R-HODE that largely retained the label (71% 2H) and to 9R-HODE that lost most of the label (22% 2H). These data indicated that P450 catalyzed abstraction of the pro-R hydrogen at C11, double bond migration and suprafacial oxygen insertion at C9 to give 9R-HODE, while abstraction of the pro-S hydrogen at C11, followed by double bond migration and oxygen insertion, yielded 13R-HODE. Hepatic microsomes of the cynomolgus monkey metabolized 18:2n-6 as above and 20:4n-6 to 13-hydroxyeicosatetraenoic acid, likely formed in analogy with 11-HODE. In summary, one mechanism in the biosynthesis of cis-trans-conjugated hydroxy fatty acids by P450 involves suprafacial hydrogen abstraction and oxygen insertion. In addition, hydrolysis of the unstable bis-allylic hydroxy metabolites may contribute to the formation of conjugated hydroxy fatty acids.

Animals↗

PubMed1987

Simultaneous liquid chromatographic determination of vanillylmandelic acid, homovanillic acid, and 5-hydroxy-3-indoleacetic acid in urine, using isocratic elution and electrochemical detection.

A method for the simultaneous measurement of vanillylmandelic acid, homovanillic acid and 5-hydroxyindoleacetic acid in urine is described. Based on reversed-phase liquid chromatography with electrochemical detection, the procedure employs isocratic elution, thus making it suitable for use in the less well-equipped clinical or research laboratory. A simple extraction of the acids from acidified urine into ethyl acetate, is followed by evaporating to dryness a portion of the organic layer, and redissolving the residue in chromatographic mobile phase. Up to 20 samples can be analysed in a single working day. The method is validated and the results obtained are compared with reference methods. The cause of contamination of the glassy carbon surface of the working electrode is investigated, and a simple electrochemical pretreatment is described that overcomes this problem. Finally, the extra clinical information that can be derived from multi-metabolite assays is considered.

Biogenic Amines↗

PubMed1974