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At least 775 records · Page 43Linked to original sources
PubMed1983

Myelin proteins: degradation in rat brain initiated by metabolites causative of maple syrup urine disease.

Maple syrup urine disease (MSUD), an inborn error of metabolism in humans, is expressed as an inability to oxidatively decarboxylate the branched-chain alpha-keto acids derived from leucine, isoleucine and valine. Rats 14 days old were injected intracranially with a solution containing leucine, alpha-ketoisocaproate, and tracer amounts of 3H-lysine. Myelin isolated from these rat brains at 28 days of age had a washed dry weight 85 per cent of controls. The protein content of the myelin prepared from treated and control rats was identical, as were the specific activities of the individual proteins separated by polyacrylamide gel electrophoresis. Myelin protein from treated rats was deficient in myelin high molecular weight proteins including glycoproteins, and degradation products of these proteins were observed in myelin of treated rats. MSUD associated metabolites in man may initiate a process leading to the proteolytic degradation of myelin proteins, thereby producing abnormal myelin sheaths.

Animals↗
PubMed1985

Inhibition of medium-chain fatty acid beta-oxidation in vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid.

Valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid, were found to inhibit strongly the metabolism of decanoic acid in homogenates of rat liver. Reductions in decanoate consumption in response to inhibitors were paralleled by decreases in the formation of octanoic and hexanoic acids, two products of decanoate beta-oxidation. In contrast, 4-pentenoic acid, an established inhibitor of long-chain fatty acid beta-oxidation, had little effect on the metabolism of decanoate. It is concluded that the title compounds are potent, broad-spectrum inhibitors of fatty acid beta-oxidation, a property which may be of key toxicological importance in the pathology of valproate-induced liver injury.

Adenosine Triphosphate↗
PubMed1985

Ester-exchange catalyzed by lipase modified with polyethylene glycol.

Lipoprotein lipase was modified with 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-s-triazine; forty-six percent out of seven amino groups in the molecule were substituted. The modified lipase catalyzed ester-exchange reactions between an ester and an alcohol, between an ester and an acid, and between two esters. The modified enzyme catalyzed these reactions not only in organic solvents, but also in straight hydrophobic substrates. As the modified enzyme was extremely stable at elevated temperature, for example at 70 degrees C, this can find many practical applications.

Caproates↗
PubMed1990

Interactions between plasticizers and fatty acid metabolism in the perfused rat liver and in vivo. Inhibition of ketogenesis by 2-ethylhexanol.

Rates of ketone body (beta-hydroxybutyrate plus acetoacetate) production by perfused livers from starved rats were decreased about 60% from 39 +/- 2 to 17 +/- 3 mumol/g/hr by 2-ethylhexanol (200 microM), a primary metabolite of the plasticizer diethylhexyl phthalate. Inhibition of ketogenesis by ethylhexanol was dose dependent (half-maximal inhibition occurred with 25 microM) in the presence or absence of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Concentrations of beta-hydroxybutyrate relative to acetoacetate (B/A) increased in a step-wise manner from 0.32 to 0.75 in the effluent perfusate when ethylhexanol was infused. In contrast, the B/A ratio decreased in parallel with inhibition of ketone body production when alcohol dehydrogenase was inhibited. Pretreatment of rats with phenobarbital, an inducer of omega and omega-1 hydroxylases, diminished inhibition of ketone body production by low (less than 50 microM) of ethylhexanol. Thus, ethylhexanol is oxidized via phenobarbital-inducible pathways to metabolites which do not inhibit ketogenesis. Studies were conducted to determine the site of inhibition of fatty acid oxidation by ethylhexanol. Rates of ketone body production in the presence of oleate (250 microM), which requires transport of the corresponding CoA compound into mitochondria, were reduced from 80 +/- 6 to 58 +/- 8 mumol/g/hr by ethylhexanol. In contrast, ketone body production from hexanoate, which is activated in the mitochondria, was not affected by ethylhexanol. Basal and oleate-stimulated rates of H2O2 production were not affected by ethylhexanol, indicating that peroxisomal beta-oxidation was not altered by the compound. Based on these data it is concluded that 2-ethylhexanol inhibits beta-oxidation of fatty acids in mitochondria but not in peroxisomes. Treatment of rats with ethylhexanol (0.32 g/kg, i.p.) decreased plasma ketone bodies from 1.6 to 0.8 mM, increased hepatic triglycerides and increased lipid predominantly in periportal regions of the liver lobule. These data indicate that alterations in hepatic fatty acid metabolism in periportal regions of the liver lobule may be early events in peroxisome proliferation.

Animals↗
PubMed1990

In vitro effects of eight-carbon fatty acids on oxidations in rat liver mitochondria.

Sodium valproate, a commonly used anticonvulsant agent, is a simple branched-chain fatty acid which interferes with beta-oxidation and ammonia metabolism in most patients, with hepatotoxic consequences in some cases. Rat liver mitochondria incubated with valproate displayed time-dependent inhibitions of state 3 oxidation rates with all the substrates tested, but most markedly with glutamate, pyruvate, alpha-ketoglutarate and acylcarnitines (Ki = 125 microM with glutamate and palmitoylcarnitine, and 24 microM with pyruvate). The inhibition of glutamate appeared to be specifically directed against the glutamate dehydrogenase pathway of this oxidation. Valproate was less effective when added to uncoupled mitochondria, suggesting the formation of an inhibitory species by an ATP-dependent mechanism. Mitochondria from clofibrate-treated rats were less sensitive to valproate inhibition. Neither fasting nor the presence of 1 mM L-carnitine affected the inhibition of beta-oxidation. The branched-chain isomer, 2-ethylhexanoic acid, had similar effects to valproate, but the straight-chain octanoic acid was totally different in its spectrum of actions on mitochondria. The data support the theory that valproate may inhibit by sequestration of CoA as valproyl-CoA, but also suggest that there are other mechanisms responsible for some of the inhibitions. Furthermore, it argued that while mitochondrial respiration is decreased, valproate is not an inhibitor of oxidative phosphorylation per se.

Animals↗
PubMed1983

Effect of increasing carbon chain length on organic acid transport by the choroid plexus: a potential factor in Reye's syndrome.

Transport of the anionic herbicide 2,4-dichlorophenoxyacetic acid by choroid plexus is inhibited significantly by several short and medium chain acids. For both monocarboxylic and dicarboxylic homologs, inhibition clearly increases with chain length. It appears that organic acid compounds of longer chain length, higher brain uptake index, and highest inhibition of choroid plexus transport would be the ones producing the most significant increases in intracranial pressure in metabolic encephalopathy such as Reye's syndrome.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1984

Formation of epsilon-hydroxycaproate and epsilon-aminocaproate from N-nitrosohexamethyleneimine: evidence that microsomal alpha-hydroxylation of cyclic nitrosamines may not always involve the insertion of molecular oxygen into the substrate.

The formation of the products of microsomal metabolism of the cyclic nitrosamine, nitrosohexamethyleneimine (NO-HEX) were studied. Information on the origins of the oxygen atoms in four major metabolites of NO-HEX was obtained by metabolizing this compound in an 18O2 atmosphere using microsomes and cytosol, beta- and gamma-Hydroxy-NO-HEX are formed as a result of the insertion of a hydroxyl group derived from molecular oxygen into NO-HEX. All of the oxygen atoms in epsilon-aminocaproate (EAC) were derived from water. Approximately half of the molecules of epsilon- hydroxycaproate ( EHC ) contain an 18O atom; thus, half of the alpha-hydroxy-NO-HEX formed incorporates a hydroxyl group derived from molecular oxygen with the remainder of the hydroxyls being from water. To account for the above data and the related metabolic origins of EAC and EHC ( Hecker and McClusky , Cancer Res., 42 (1982) 59; Hecker et al., Teratogen. Carcinogen. Mutagen (1982) in press), we have proposed a mechanism for the formation of these compounds from cyclic nitrosamines catalyzed by microsomal and cytosolic enzymes.

Aminocaproates↗
PubMed1988

Induction of cytosolic and microsomal epoxide hydrolases in mouse liver by peroxisome proliferators, with special emphasis on structural analogues of 2-ethylhexanoic acid.

Using dietary administration, mice were exposed to eight substances known to cause peroxisome proliferation (i.e. clofibrate clofibric acid, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, nafenopin, ICI-55.897, S-8527 and Wy-14.643) or the related substance p-chlorophenoxyacetic acid (group A). Other animals received di(2-ethylhexyl)phthalate, mono(2-ethylhexyl)phthalate, 2-ethylhexanoic acid, or one of 12 other metabolically and/or structurally related compounds (group B). The effects of these treatments on liver cytosolic and microsomal epoxide hydrolases, microsomal cytochrome P-450, cytosolic glutathione transferase activity, the liver-somatic index and the protein contents of the microsomal and cytosolic fractions prepared from liver were subsequently monitored. In general, peroxisome proliferation was accompanied by increases in cytosolic epoxide hydrolase activity. Many peroxisome proliferators also caused increases in microsomal epoxide hydrolase activity, although the correlation was poorer in this case. Immunochemical quantitation by radial immunodiffusion demonstrated that the increases observed in both of these enzyme activities reflected equivalent increases in enzyme protein, i.e. that induction truly occurred. Induction of total microsomal cytochrome P-450 was obtained after dietary exposure to clofibrate, clofibric acid, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, nafenopin, Wy-14.643, di(2-ethylhexyl)phthalate and di(2-ethylhexyl)phosphate. The most pronounced effects on cytosolic glutathione transferase activity were the decreases obtained after treatment with clofibrate, clofibric acid and Wy-14.643. Our results, together with those reported by others, suggest that the processes of peroxisome proliferation and induction of cytosolic epoxide hydrolase are intimately related. One possible explanation for this is presented.

Animals↗