On the mechanisms of some pharmacological actions of the hypoglycaemic toxins hypoglycin and pent-4-enoic acid. A way out of the present confusion

Sherratt, H. S. A.; Osmundsen, Harald

doi:10.1016/0006-2952(76)90139-8

Cited by 84 publications

(31 citation statements)

References 41 publications

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“…14C-labeled acid-soluble P-oxidation products from [U-14C]palmitic acid or [l-14C]palmitic acid were directly counted in the supernatant. Such products mainly represent ketone bodies and, to a small extent, citric acid cycle intermediates (28,29,40). We verified from measurement of the KCN-inhibitable activity that mitochondria mediated at least 80% of the oxidation of [U-14C]palmitate (41).…”

Section: Methodsmentioning

confidence: 80%

Decreased mitochondrial oxidation of fatty acids in pregnant mice: Possible relevance to development of acute fatty liver of pregnancy

et al. 1993

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Severe impairment of the beta-oxidation of fatty acids, as a consequence of a single factor or a combination of different causes, leads to microvesicular steatosis of the liver. In an effort to understand the mechanism(s) leading to the development of acute fatty liver of pregnancy in some women, we determined the effects of pregnancy on the mitochondrial oxidation of fatty acids in mice. In vivo, the rate of oxidation of the whole fatty-acid chain length was determined by measuring the rate of exhalation of [14C]CO2 after intragastric administration of a tracer dose of [U-14C]palmitic acid. [14C]CO2 exhalation was not significantly decreased at 14 days of gestation, but it had declined by 40% at 18 days of gestation (i.e., 24 to 48 hr before delivery). The rate of first beta-oxidation cycle was assessed by measuring the rate of [14C]CO2 exhalation after administration of [1-14C]octanoic acid, [1-14C]butyric acid or [1-14C]palmitic acid. [14C]CO2 exhalation had declined by 60%, 46%, and 24% after administration of [1-14C]octanoic acid, [1-14C]butyric acid and [1-14C]palmitic acid, respectively, in 18-day-pregnant mice. Total hepatic lipids and triglycerides, expressed per gram of liver, remained unchanged in 18-day-pregnant mice. In vitro, the rate of mitochondrial beta-oxidation (expressed per milligram of protein) had decreased by 47% at 18 days' gestation with [U-14C]palmitic acid as substrate and by 33% with [1-14C]octanoic acid but remained unchanged with [1-14C]palmitic acid. The activity of the tricarboxylic acid cycle, assessed by the formation of [14C]CO2 from [1-14C]acetic acid, had decreased by 24%. We conclude that the mitochondrial oxidation of fatty acids decreased during late-term pregnancy in mice as a consequence of both decreased mitochondrial beta-oxidation of medium-chain fatty acids, and decreased activity of the tricarboxylic acid cycle. We suggest that this effect, in combination with other factors, may contribute to the development of fatty liver of pregnancy in some pregnant women.

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Section: Methodsmentioning

confidence: 80%

Decreased mitochondrial oxidation of fatty acids in pregnant mice: Possible relevance to development of acute fatty liver of pregnancy

et al. 1993

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“…Hypoglycin and 4-PA produce dicarboxylic aciduria and other common sequelae by different mechanisms (12)(13)(14). The coenzyme A (CoA) ester of a metabolite of hypoglycin inhibits short-chain CoA dehydrogenases acting on isovaleric, 2-methylbutyric, butyric and glutaric acids (13)(14)(15)(16)(17)(18).…”

Section: Discussion Indicators Of Abnormal Intermediary Metabolismmentioning

confidence: 99%

The Hepatotoxicity of Valproic Acid and Its Metabolites in Rats. II. Intermediary and Valproic Acid Metabolism

et al. 1984

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The role of metabolites in valproic acid (VPA)-associated hepatotoxicity was studied in rats. The most steatogenic mono-unsaturated metabolite, 4-en-VPA, caused the greatest changes in indicators of beta-oxidation inhibition (dicarboxylic aciduria, beta-hydroxybutyrate reduction); however, the biochemical effects were much less pronounced than those reported for hypoglycin. Steatosis in VPA-treated rats occurred only at nearly lethal doses. Phenobarbital induction was confirmed as a predisposing factor; however, it appeared not to greatly enhance production of 4-en-VPA or its recognized metabolites, which collectively comprised only 0.5% of the dose. Elevated oxo-VPA metabolites in serum and 2-propylglutarate in liver were associated with toxicity. Among the newly discovered minor metabolites with possible biologic effects were diols (suggesting epoxide precursors) and a series of dienes and trienes. The rarity of severe human hepatotoxicity indicates that, normally, beta-oxidation inhibition is compensated, and cellular defense mechanisms prevail over reactive metabolites. This requires adequate nutrition; on the other hand, severe glycogen depletion may promote toxicity by compromising glucuronidation, the major clearance route. Other literature comments are also supported: (i) caution is indicated for patients with various unusual congenital disorders (e.g., organic acidurias or other mitochondrial defects), and (ii) monotherapy obviates both the predisposition to toxicity and the requirement of large doses to produce therapeutic levels.

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“…(measured polarographically using a Clarke type 02 electrode) stoichiometrically reflects the ,-oxidation of the acyl-L-carnitine. A fuller explanation of this system has been given by Sherratt and Osmundsen (50 (Fig. 1).…”

Section: Fatty Acid Oxidation By Isolated Mitochondriamentioning

confidence: 91%

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Elcombe¹,

Mitchell²

1986

Environ Health Perspect

163

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The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (13-oxidation; cyanide-insensitive palmitoyl CoA oxidase) and concomitant increases in the number of peroxisomes. Similar treatment of cultured guinea pig, marmoset, or human hepatocytes revealed little or no effect of MEHP. In order to eliminate possible confounding influences of biotransformation, the proximate peroxisome proliferator(s) derived from MEHP have been identified. Using cultured hepatocytes these agents were found to be metabolite VI [mono(2-ethyl-5-oxohexyl) phthalate] and metabolite IX [mono(2-ethyl-5-hydroxyhexyl) phthalate]. The addition of these "active" metabolites to cultured guinea pig, marmoset, or human hepatocytes again revealed little effect upon peroxisomes or related enzyme activities (peroxisomal 1-oxidation or microsomal lauric acid hydroxylation). These studies demonstrate a marked species difference in the response of hepatocytes to MEHP-elicited peroxisome proliferation. Preliminary studies have also suggested that peroxisome proliferation due to MEHP may be due to an initial biochemical lesion of fatty acid metabolism.

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On the mechanisms of some pharmacological actions of the hypoglycaemic toxins hypoglycin and pent-4-enoic acid. A way out of the present confusion

Cited by 84 publications

References 41 publications

Decreased mitochondrial oxidation of fatty acids in pregnant mice: Possible relevance to development of acute fatty liver of pregnancy

Decreased mitochondrial oxidation of fatty acids in pregnant mice: Possible relevance to development of acute fatty liver of pregnancy

The Hepatotoxicity of Valproic Acid and Its Metabolites in Rats. II. Intermediary and Valproic Acid Metabolism

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

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