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PubMed1987

Inhibitory effect of gentamicin on gluconeogenesis from pyruvate, propionate, and lactate in isolated rabbit kidney-cortex tubules.

The effect of gentamicin on glucose production in isolated rabbit renal tubules was studied with lactate, propionate, malate, 2-oxoglutarate, and succinate as substrates. This antibiotic at 5 mM concentration inhibited gluconeogenesis from lactate by about 60% and that from either pyruvate or propionate by about 30%. In contrast, it did not alter the rate of glucose formation from other substrates studied. The rate of gluconeogenesis was higher at 1 mM propionate than at increasing concentrations of this substrate and was stimulated in the presence of 1 mM carnitine. However, the addition of carnitine did not affect the degree of inhibition of glucose formation by gentamicin. Since the mitochondrial free coenzyme A level was significantly lower in the presence of 10 than 1 mM propionate and increased on the addition of carnitine to the reaction medium, the inhibitory effect of propionate concentrations above 1 mM on gluconeogenesis in rabbit renal tubules may be due to a depletion of the free mitochondrial coenzyme A level, resulting in an inhibition of the mitochondrial coenzyme A-dependent reactions. In intact rabbit kidney cortex mitochondria incubated in State 4 as well as in Triton X-100-treated mitochondria, 5 mM gentamicin inhibited by about 30-40% the incorporation of 14CO2 into both pyruvate and propionate. The results indicate that the inhibitory effect of gentamicin on glucose formation in isolated kidney tubules incubated with lactate, pyruvate, or propionate is likely due to a decrease of the rate of carboxylation reactions.

Animals↗
PubMed1991

Effects of methylmalonate and propionate on uptake of glucose and ketone bodies in vitro by brain of developing rats.

Methylmalonate (MMA) and propionate effects on glucose and ketone body uptake in vitro by brain of fed and 30-hour-fasted 15-day-old rats were studied. In some experiments cerebrum prisms were incubated in the presence of glucose and either MMA or propionate in Krebs-Ringer bicarbonate buffer, pH 7.0. In others, the incubation medium contained beta-hydroxybutyrate (HBA) or acetoacetate (AcAc) instead of glucose. We verified that MMA increased glucose uptake by brain of fasting animals, whereas propionate had no effect. In addition, MMA diminished HBA but not AcAc incorporation into brain prisms, whereas propionate provoked a diminished utilization of both ketone bodies by brain. The in vitro effect of MMA and propionate on brain and liver beta-hydroxybutyrate dehydrogenase activity was also investigated. It was shown that MMA but not propionate significantly inhibited this activity. Rats were also injected subcutaneously three times with a MMA buffered solution, and the in vivo effects of MMA on the above-mentioned parameters assessed. Results from these experiments confirmed the previously found in vitro MMA effects. Methylmalonic acidemic patients accumulate primarily methylmalonate and secondarily propionate and other metabolites in their tissues at levels comparable to those we used in our assays. Most patients who survive early stages of the disease show a variable degree of neuromotor delay. Since glucose and sometimes ketones are the vital substrates for brain metabolism, it is possible that our findings may contribute to a certain extent to an understanding of the biochemical basis of mental retardation in these patients.

3-Hydroxybutyric Acid↗
PubMed1991

Propionate mitochondrial toxicity in liver and skeletal muscle: acyl CoA levels.

Propionic acidemia occasionally produces a toxic encephalopathy resembling Reye syndrome, indicating disruption of mitochondrial metabolism. Understanding the mitochondrial effect of propionate might clarify the pathophysiology. Liver mitochondria are inhibited by propionate (5 mM) while muscle mitochondria are not. Preincubation is required to inhibit liver mitochondria, suggesting that propionate is metabolized to propionyl CoA. Liver and skeletal muscle mitochondria incubated with [1-14C]propionate contain similar quantities of matrix isotope and release comparable [14C]CO2. However, only liver mitochondria accumulated significant propionyl CoA, which was largely (68%) synthesized from propionate. Carnitine reduced the level of liver matrix propionyl CoA. Inhibition of respiratory control ratios by propionate correlated with propionyl CoA levels. These results support the hypothesis that acyl CoA esters are toxic and that carnitine exerts its protective effect by converting acyl CoA esters to acylcarnitine esters.

Acyl Coenzyme A↗
PubMed2006

Metabolic changes associated with hyperammonemia in patients with propionic acidemia.

Propionic acidemia is an autosomal recessive disorder caused by deficiency of propionyl CoA carboxylase. Affected patients can develop severe hyperammonemia, whose causative mechanism is unknown. In this study, we monitored changes in metabolic parameters associated with hyperammonemia in patients with propionic acidemia. Levels of ammonia were correlated with plasma levels of individual amino acids and carnitine and with urinary organic acids. Significance of correlations was determined with analysis of variance. Hyperammonemia positively correlated with an increase in branched-chain amino acids (leucine and isoleucine) and a decrease in glutamine/glutamate and esterified carnitine. The urinary excretion of methylcitric acid, formed by the combination of propionic acid with oxaloacetate from the Krebs cycle, increased while that of citric acid decreased with hyperammonemia. These results suggest that in propionic acidemia, hyperammonemia is triggered by catabolism with the accumulation of propionic acid derivatives. The decrease of the plasma levels of glutamine/glutamate with hyperammonemia in patients with propionic acidemia indicates that the mechanism producing hyperammonemia differs from that in urea cycle defects. The increase in methylcitric acid and decline in citric acid urinary excretion suggest that hyperammonemia in propionic acidemia might be related to inability to maintain adequate levels of glutamine precursors through a dysfunctional Krebs cycle.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Propionic acid metabolism and poly-3-hydroxybutyrate-co-3-hydroxyvalerate (P3HB-co-3HV) production by Burkholderia sp.

Mutants of Burkholderia sp. that are unable to grow on propionic acid (prp) but still accumulate P3HB-co-3HV from carbohydrate and propionic acid were studied. In shaken flask tests, yields of 3HV from propionic acid (Y(3HV/Prop)) increased from 0.10 g g(-1) in the wild type to c.a. 0.35 g g(-1) in mutants affected in alpha-oxidation pathway or to 0.80 g g(-1) in mutants not affected in that pathway. In bioreactor tests, mutant IPT 189 showed Y(3HV/Prop) = 1.20 g g(-1), a yield very close to the theoretical maximum of 1.35 g g(-1). Accumulation of 3HV units from unrelated carbon sources was undetectable in these mutants indicating that 3HV units are produced directly from propionic acid. Thus, the industrial use of those mutants to produce the copolymer from sucrose and propionic acid could significantly reduce the production costs. The results strongly suggest the existence of at least two pathways that are involved in the oxidation of propionic acid in Burkholderia sp. Their rates would be modulated by the availability of propionic acid.

Bioreactors↗
PubMed1997

Acetate and propionate potentiate the antiproliferative effect of butyrate on RBL-2H3 growth.

1. The effect of acetate, propionate, and butyrate separately and combined on RBL-2H3 (a rat basophilic leukemic cell type) proliferation during 24, 48, and 72 hr was examined. Also, the effect of a mixture of the three volatile fatty acids on proliferation of HeLa-155 (a human adenocarcinoma), C57 B1/6J (a mouse melanoma), and MCF-7 (human breast tumor) during 8 days was investigated. 2. Acetate and propionate per se did not present any effect on RBL-2H3 growth during 72 hr, however, when acetate and propionate were added together a significant inhibition of this cell growth was found; 18% for 48 and 37% for 72 hr. The addition of butyrate to the culture medium caused a 75% decrease in the rate of this cell growth either after 48 and 72 hr. This effect of butyrate was pronounced by acetate (86% and 90% for 48 and 72 hr, respectively), propionate (87% for 48 and 93% for 72 hr), and acetate and propionate together (76% for 48 and 92% for 72 hr). 3. Daily addition of a mixture of the short-chain fatty acids (10 mM acetate, 2 mM propionate and 1.5 mM butyrate) markedly decreased the number of cells after 8 days: 58% for RBL-2H3, 42% for HeLa-155, 91% for C57 B1/6J and 55% for MCF-7. 4. These results support the proposition that a fiber-rich diet that leads to great production of butyrate but also of propionate and acetate would be more effective to prevent the occurrence of colorectal cancer than the administration of this short-chain fatty acid given alone.

Acetates↗
PubMed1967

The regulation of propionate oxidation in Prototheca zopfii.

1. Whole cell suspensions of Prototheca zopfii grown on propionate oxidize propionate, acrylate, malonic semialdehyde and acetate immediately, whereas acetate-grown cells only oxidize acrylate or propionate rapidly after a lag of 20-30min. This adaptation to propionate is slowed down by 8-azaguanine or p-fluorophenylalanine, and is not influenced by adding an ammonium salt or an amino acid mixture. 2. The adaptation involves induction of the enzymes of beta-oxidation of propionate. 3. A small proportion (5-8%) of the activities of propionyl-CoA dehydrogenase, beta-hydroxypropionate dehydrogenase and malonic semialdehyde dehydrogenase are consistently associated with mitochondria isolated from propionate-grown cells. 4. Such mitochondria will oxidize propionyl-CoA, beta-hydroxypropionate and malonic semialdehyde, and the respiration rates with these substrates in the presence of inorganic phosphate are ADP-dependent. 5. Mitochondria from acetate-grown cells do not contain detectable activities of the enzymes of propionate oxidation.

Acetates↗
PubMed1972

Extent of propionate metabolism during absorption from the bovine ruminoreticulum.

1. Solutions containing acetate, [2-(14)C]propionate and butyrate were placed into the ruminoreticulum of calves to measure the extent to which propionate is metabolized by ruminoreticulum epithelium. In response to five different combinations of pH and total volatile fatty acid concentrations, propionate absorption rates ranged from 89 to 341mmol/h. 2. The extent of propionate conversion into lactate, calculated from both concentration and specific radioactivity in portal and arterial blood, averaged 4.9 (range 2.5-9.1)%. 3. Circulating glucose synthesized from propionate had a higher specific radioactivity than arterial lactate and was converted into lactate by gastrointestinal tissues. Thus conversion of propionate into lactate was overestimated but was corrected to average 2.3 (1.0-4.6)%. 4. The estimates of propionate conversion into lactate were negatively correlated with its rate of absorption.

Absorption↗
PubMed1988

Effects of propionate and carnitine on the hepatic oxidation of short- and medium-chain-length fatty acids.

Accumulation of propionate, or its metabolic product propionyl-CoA, can disrupt normal cellular metabolism. The present study examined the effects of propionate, or propionyl-CoA generated during the oxidation of odd-chain-length fatty acids, on hepatic oxidation of short- and medium-chain-length fatty acids. In isolated hepatocytes, ketone-body formation from odd-chain-length fatty acids was slow as compared with even-chain-length fatty acid substrates, and increased as the carbon chain length was increased from five to seven to nine. In contrast, rates of ketogenesis from butyrate, hexonoate and octanoate were all approximately equal. Propionate (10 mM) inhibited ketogenesis from butyrate, hexanoate and octanoate by 81%, 53% and 18% respectively. Addition of carnitine had no effect on ketogenesis from the even-chain-length fatty acids, but increased the rate of ketone-body formation from pentanoate (by 53%), heptanoate (by 28%) and from butyrate or hexanoate in the presence of propionate. The inhibitory effect of propionate could not be explained by shunting acetyl-CoA into the tricarboxylic acid cycle, as CO2 formation from butyrate was also decreased by propionate. Examination of the hepatocyte CoA pool during oxidation of butyrate demonstrated that addition of propionate decreased acetyl-CoA and CoA as propionyl-CoA accumulated. Addition of carnitine decreased propionyl-CoA by 50% (associated with production of propionylcarnitine) and increased acetyl-CoA and CoA. Similar changes in the CoA pool were seen during the oxidation of pentanoate. These results demonstrate that accumulation of propionyl-CoA results in inhibition of short-chain fatty acid oxidation. Carnitine can partially reverse this inhibition. Changes in the hepatocyte CoA pool are consistent with carnitine acting by generating propionylcarnitine, thereby decreasing propionyl-CoA and increasing availability of free CoA. The data provide further evidence of the potential cellular toxicity from organic acid accretion, and supports the concept that carnitine's interaction with the cellular CoA pool can have a beneficial effect on cellular metabolism and function under conditions of unusual organic acid accumulation.

Animals↗
PubMed1991

Interaction between colonic acetate and propionate in humans.

Animal studies suggest that propionate, derived from colonic carbohydrate fermentation, may be gluconeogenic and inhibit cholesterol synthesis in the liver. We therefore studied, in six healthy subjects, the effect of rectally infused solutions containing acetate alone (180 mmol), propionate alone (180 mmol), or a mixture of acetate (180 mmol) and propionate (60 mmol). Relative to the control infusion of normal saline, acetate increased serum cholesterol, glucagon, and acetate concentrations and reduced free fatty acids (FFAs) within 30 min. Propionate alone increased serum propionate, glucose, and glucagon with no effects on cholesterol and a delayed fall in FFAs. The addition of propionate to acetate resulted in no significant rise in serum cholesterol. These results are consistent with the hypothesis that colonic propionate is a gluconeogenic substrate in humans and inhibits the utilization of acetate for cholesterol synthesis.

Acetates↗
PubMed2004

L-Rhamnose increases serum propionate in humans.

BACKGROUND: Acetic and propionic acids are produced by colonic bacterial fermentation of unabsorbed carbohydrates and are absorbed into the portal circulation. From there, they travel to the liver, where acetate is a lipogenic substrate and propionate can inhibit lipogenesis. The extent to which peripheral blood short-chain fatty acid concentrations reflect differences in colonic fermentation is uncertain. The unabsorbed sugar lactulose produces mainly acetate when fermented in vitro, whereas L-rhamnose yields propionate. OBJECTIVE: The objective of the study was to ascertain whether ingestion of L-rhamnose and lactulose would have different acute effects on peripheral acetate and propionate concentrations and on breath hydrogen and methane concentrations. DESIGN: Twenty-two subjects were fed 25 g L-rhamnose, lactulose, or glucose on 3 separate occasions in a randomized crossover design. Blood and breath samples were collected hourly for 12 h. RESULTS: Serum propionate was significantly higher with ingestion of L-rhamnose than with that of lactulose or glucose (P < 0.001). The area under the curve for serum acetate was significantly higher with ingestion of lactulose than with that of glucose (P < 0.03). The ratio of serum acetate to propionate was significantly higher with ingestion of lactulose than with that of glucose or L-rhamnose (P < 0.01). Breath hydrogen was significantly higher with ingestion of lactulose than with that of L-rhamnose or glucose (P < 0.0001). CONCLUSIONS: The selective increases in serum acetate and propionate concentrations in humans were obtained by feeding specific fermentable substrates. Presumably, these changes in serum concentrations reflect changes in colonic production. Selective alteration of colonic fermentation products could yield a new mechanism for modifying blood lipids.

Acetates↗
PubMed1990

Comparison between physiological effects of konjac-glucomannan and propionate in baboons fed "Western" diets.

Dietary fiber and resistant starch are fermented by colonic bacteria to short-chain fatty acids (SCFA) such as acetic, butyric and propionic acid, which the colon absorbs. It has been suggested that the beneficial metabolic effects of dietary fiber may be mediated through propionate. We therefore compared the effects of a soluble dietary fiber concentrate, konjac-glucomannan (K-GM), and of propionate on plasma fibrinogen, serum and liver lipid, glucose tolerance, insulin response and liver glycogen in baboons. Twelve male baboons were fed a "Western" diet with or without K-GM (5%) or sodium propionate (2%) supplements for periods of 9 wk in a crossover, randomized order, with stabilization periods in between. Measurements were taken at baseline and after 4 and 9 wk of each study period. After 9 wk, total serum cholesterol levels were significantly higher than pretest values when baboons consumed the unsupplemented Western diet (25%, p less than 0.05) or the propionate diet (17%, p less than 0.05). Konjac-glucomannan prevented this increase. The high density lipoprotein cholesterol concentration increased with all experimental diets (p less than 0.05). The percentage of total cholesterol as high density lipoprotein cholesterol, was significantly higher with K-GM supplementation than with the other diets. Konjac-glucomannan supplementation also resulted in lower than baseline values for triglycerides (p less than 0.01) and circulating free fatty acids (p less than 0.05) after 9 wk. Only the propionate diet raised serum triglycerides significantly (by 6%) above baseline. Liver cholesterol concentration was 31-34% lower, and the area under the glucose tolerance curve was smaller with K-GM and propionate diets (p less than 0.05) than with the unsupplemented diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Hypophagic effects of ammonium are greater when infused with propionate compared with acetate in lactating dairy cows.

The objective of this experiment was to determine interactions between hypophagic effects of propionate and ammonium in lactating dairy cows. Eight ruminally cannulated Holstein cows in mid-lactation were used in a duplicated 4 x 4 Latin square design experiment with a 2 x 2 factorial arrangement of treatments. Factors evaluated were type of volatile fatty acid (VFA; acetate vs. propionate) and type of salt (sodium vs. ammonium). Treatment solutions were infused continuously into the rumen at a rate of 16.7 mmol of VFA salts/min starting 2 h before feeding and ending 12 h after feeding. Hypophagic effects of ammonium were significantly greater for cows infused with propionate (4.3 vs. 12.1 kg/12 h; SEM = 1.3) compared with acetate (13.5 vs. 15.3 kg/12 h; SEM = 1.3; interaction P < 0.01). This interaction was attributed to a greater reduction in meal frequency for ammonium treatment compared with sodium treatment when infused with propionate (3.9 vs. 7.2/12 h; SEM = 0.8) compared with acetate (6.6 vs. 7.0/12 h; SEM = 0.8), indicating that infusion of ammonium propionate reduced hunger. Meal size was decreased by infusion of propionate compared with acetate, but was not affected by ammonium compared with sodium, indicating that ammonium did not affect satiety. Mechanisms to explain the interactions between ammonium and propionate on meal frequency and feed intake warrant further investigation.

Animals↗
PubMed1985

Mechanisms of growth inhibition by propionate and restoration of the growth by sodium bicarbonate or acetate in Rhodopseudomonas sphaeroides S.

Mechanisms of growth inhibition by propionate on the growth of Rhodopseudomonas sphaeroides were studied. Partially purified pyruvate dehydrogenase complex (PDC) from R. sphaeroides was inhibited by propionyl-CoA, one of the metabolic intermediates of propionate, while propionate itself did not inhibit the enzyme. This suggests that the inhibitor of the growth in vivo is not propionate but propionyl-CoA. The inhibition by propionyl-CoA was competitive with respect to coenzyme A concentration. The K1 value for propionyl-CoA was 0.84 mM. Addition of NaHCO3, which restored the growth of this bacterium in the presence of propionate, increased the rate of propionate incorporation by 1.7-fold and decreased the intracellular level of propionyl-CoA by half. These findings suggest that HCO3-ion lowers the level of propionyl-CoA by accelerating its carboxylation reaction, which is catalyzed by propionyl-CoA carboxylase. Effects of NaHCO3 and acetate on the growth restoration were also studied by the use of propionyl-CoA carboxylase-deficient mutants. NaHCO3 did not restore the growth of the mutants, indicating an essential role of propionyl-CoA carboxylase on the restoration of growth by NaHCO3 as suggested above. Addition of acetate restores the growth of the mutants in the presence of propionate. Acetate probably restores the growth by supplying acetyl-CoA.

Acetates↗
PubMed1998

Inhibition of Na+,K+-ATPase from rat brain cortex by propionic acid.

Buffered propionic acid was injected s.c. into rats twice a day at 8 h intervals from the 6 to 21 days of age. Control rats received saline in the same volumes. The animals were weighed and killed by decapitation at 23 days. Whole brain and cerebral cortex were weighed and synaptic plasma membranes were prepared from cortex for the determination of Na+,K+-ATPase and Mg2+-ATPase activities. Body, whole brain and cortical weights were similar in the two groups, suggesting that propionic acid does not cause malnutrition in rats. Na+,K+-ATPase activity was significantly reduced by 30% in membranes from the propionate-treated group, whereas Mg2+-ATPase activity was not. In another set of experiments, synaptic plasma membranes were prepared from cerebral cortex of 23-day-old rats and incubated with propionic acid at final concentrations ranging from 0.1 to 2.0 mM. Na+,K+-ATPase activity, but not Mg2+-ATPase activity, was inhibited by 22-32%. Since propionic acid concentrations in plasma of chronically treated rats and of propionic acidemic children are of the same order of magnitude as those tested in vitro, the results suggest that the inhibition of Na+,K+-ATPase activity may be related to the neurological dysfunction of patients affected by propionic acidaemia.

Animals↗
PubMed2001

The methylcitric acid pathway in Ralstonia eutropha: new genes identified involved in propionate metabolism.

From Ralstonia eutropha HF39 null-allele mutants were created by Tn5 mutagenesis and by homologous recombination which were impaired in growth on propionic acid and levulinic acid. From the molecular, physiological and enzymic analysis of these mutants it was concluded that in this bacterium propionic acid is metabolized via the methylcitric acid pathway. The genes encoding enzymes of this pathway are organized in a cluster in the order prpR, prpB, prpC, acnM, ORF5 and prpD, with prpR transcribed divergently from the other genes. (i) prpC encodes a 2-methylcitric acid synthase (42720 Da) as shown by the measurement of the respective enzyme activity, complementation of a prpC mutant of Salmonella enterica serovar Typhimurium and high sequence similarity. (ii) For the translational product of acnM the function of a 2-methyl-cis-aconitic acid hydratase (94726 Da) is proposed. This protein and also the ORF5 translational product are essential for growth on propionic acid, as revealed by the propionic-acid-negative phenotype of Tn5-insertion mutants, and are required for the conversion of 2-methylcitric acid into 2-methylisocitric acid as shown by the accumulation of the latter, which could be purified as its calcium salt from the supernatants of these mutants. In contrast, inactivation of prpD did not block the ability of the cell to use propionic acid as carbon and energy source, as shown by the propionic acid phenotype of a null-allele mutant. It is therefore unlikely that prpD from R. eutropha encodes a 2-methyl-cis-aconitic acid dehydratase as proposed recently for the homologous prpD gene from S. enterica. (iii) The translational product of prpB encodes 2-methylisocitric acid lyase (32314 Da) as revealed by measurement of the respective enzyme activity and by demonstrating accumulation of methylisocitric acid in the supernatant of a prpB null-allele mutant. (iv) The expression of prpC and probably also of the other enzymes is regulated and is induced during cultivation on propionic acid or levulinic acid. The putative translational product of prpR (70895 Da) exhibited high similarities to PrpR of Escherichia coli and S. enterica, and might represent a transcriptional activator of the sigma-54 family involved in the regulation of the other prp genes. Since the prp locus of R. eutropha was very different from those of E. coli and S. enterica, an extensive comparison of prp loci available from databases and literature was done, revealing two different classes of prp loci.

Alleles↗
PubMed2004

On the mechanism of action of the antifungal agent propionate.

Propionate is used to protect bread and animal feed from moulds. The mode of action of this short-chain fatty acid was studied using Aspergillus nidulans as a model organism. The filamentous fungus is able to grow slowly on propionate, which is oxidized to acetyl-CoA via propionyl-CoA, methylcitrate and pyruvate. Propionate inhibits growth of A. nidulans on glucose but not on acetate; the latter was shown to inhibit propionate oxidation. When grown on glucose a methylcitrate synthase deletion mutant is much more sensitive towards the presence of propionate in the medium as compared to the wild-type and accumulates 10-fold higher levels of propionyl-CoA, which inhibits CoA-dependent enzymes such as pyruvate dehydrogenase, succinyl-CoA synthetase and ATP citrate lyase. The most important inhibition is that of pyruvate dehydrogenase, as this affects glucose and propionate metabolism directly. In contrast, the blocked succinyl-CoA synthetase can be circumvented by a succinyl-CoA:acetate/propionate CoA-transferase, whereas ATP citrate lyase is required only for biosynthetic purposes. In addition, data are presented that correlate inhibition of fungal polyketide synthesis by propionyl-CoA with the accumulation of this CoA-derivative. A possible toxicity of propionyl-CoA for humans in diseases such as propionic acidaemia and methylmalonic aciduria is also discussed.

ATP Citrate (pro-S)-Lyase↗
PubMed1996

Effects of propionic acid and pravastatin on HMG-CoA reductase activity in relation to forestomach lesions in the rat.

Administration of 4% propionic acid in powdered diet to rats for 12 weeks induces severe hyperplastic lesions in the forestomach mucosa. The mechanisms underlying this damage are not yet clear. Several lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors such as lovastatin and simvastatin produce forestomach lesions similar to propionic acid after oral administration and the degree of alterations is correlated with their in vitro inhibitory potency (Kloss et al. 1991). Therefore it is possible, that sustained inhibition of HMG-CoA reductase and induction of hyperplasias may be somehow connected. For that reason we investigated, whether or not propionic acid has any influence on HMG-CoA reductase activity in vitro and in vivo, because propionic acid has been suggested to suppress liver cholesterol synthesis, and also whether or not pravastatin, a more polar HMG-CoA reductase inhibitor than lovastatin displays similar effects on forestomach mucosa. In untreated forestomach microsomes in vitro, propionic acid at a concentration of 51 mM (pH 5.7) inhibited HMG-CoA reductase activity by 51 + or - 10%, but at pH 7.2 no inhibition of the enzyme could be detected. Furthermore 4% propionic acid-treatment did not lower serum cholesterol. In contrast to lovastatin (Kloss et al. 1991), oral administration of pravastatin (up to 25% in the diet) did not produce any forestomach lesions in the rat. On the other hand, pretreatment with pravastatin revealed that HMG-CoA reductase activity in microsomes exceeded the activity of control forestomach and liver microsomes by 4.9 fold and 6.7 fold respectively, whereas no induction of this enzyme (neither liver nor forestomach) could be observed by pretreatment with 4% propionic acid for 12 weeks. Despite increased hepatic HMG-CoA reductase activity, pravastatin-treatment significantly lowered serum cholesterol levels of rats. These results show that sustained inhibition of HMG-CoA reductase activity in forestomach microsomes is not strongly connected with hyperplasia development.

Animals↗