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The influence of chronic L-carnitine supplementation on the formation of preneoplastic and atherosclerotic lesions in the colon and aorta of male F344 rats.

ABSTRACT: L-Carnitine, a key component of fatty acid oxidation, is nowadays being extensively used as a nutritional supplement with allegedly "fat burning" and performance-enhancing properties, although to date there are no conclusive data supporting these claims. Furthermore, there is an inverse relationship between exogenous supplementation and bioavailability, i.e., fairly high oral doses are not fully absorbed and thus a significant amount of carnitine remains in the gut. Human and rat enterobacteria can degrade unabsorbed L-carnitine to trimethylamine or trimethylamine-N-oxide, which, under certain conditions, may be transformed to the known carcinogen N-nitrosodimethylamine. Recent findings indicate that trimethylamine-N-oxide might also be involved in the development of atherosclerotic lesions. We therefore investigated whether a 1-year administration of different L-carnitine concentrations (0, 1, 2 and 5 g/l) via drinking water leads to an increased incidence of preneoplastic lesions (so-called aberrant crypt foci) in the colon of Fischer 344 rats as well as to the appearance of atherosclerotic lesions in the aorta of these animals. No significant difference between the test groups regarding the formation of lesions in the colon and aorta of the rats was observed, suggesting that, under the given experimental conditions, L-carnitine up to a concentration of 5 g/l in the drinking water does not have adverse effects on the gastrointestinal and vascular system of Fischer 344 rats.

SUBMITTER: Empl MT

PROVIDER: S-EPMC7079849 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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The influence of chronic L-carnitine supplementation on the formation of preneoplastic and atherosclerotic lesions in the colon and aorta of male F344 rats.

Empl Michael T MT Kammeyer Patricia P Ulrich Reiner R Joseph Jan F JF Parr Maria K MK Willenberg Ina I Schebb Nils H NH Baumgärtner Wolfgang W Röhrdanz Elke E Steffen Christian C Steinberg Pablo P

Archives of toxicology 20140828 11

L-Carnitine, a key component of fatty acid oxidation, is nowadays being extensively used as a nutritional supplement with allegedly "fat burning" and performance-enhancing properties, although to date there are no conclusive data supporting these claims. Furthermore, there is an inverse relationship between exogenous supplementation and bioavailability, i.e., fairly high oral doses are not fully absorbed and thus a significant amount of carnitine remains in the gut. Human and rat enterobacteria ...[more]

PMID: 25164827

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Project description:Cancer as a multistage process can be reversed or blocked by using chemopreventive agents. Colon cancer chemoprevention has been widely investigated using cyclooxygenase inhibitors and many other chemicals of synthetic or natural origin. This particular study was carried out to assess the colon cancer chemopreventive effect of hydro-methanol extract of Rumex abyssinicus rhizome on rats.Colon cancer chemopreventive potential of hydro-methanol extract of Rumex abyssinicus rhizome was determined based on the number and multiplicity of aberrant crypt foci (ACF). Fifteen DMH (1, 2-dimethylhydrazine) treated and five untreated Wistar female rats were used. DMH was administered subcutaneously 30 mg/kg, after its pH was adjusted to 6.5-7. Treatment groups started receiving extract after six weeks of weekly DMH injections. The rats were divided in to four groups: Group 1 received only oral normal saline, Group 2 received DMH and normal saline, Group 3 and 4 received DMH plus 250 mg/kg and 500 mg/kg extract, respectively. Specific phytoconstituents of the plant, which were reviewed from original articles, were virtually evaluated for cyclooxygenase-2 (COX-2) inhibition. The binding energies and interactions of the phytochemicals from Rumex abyssinicus against COX-2 were determined by Autodock4.2.There was a statistically significant reduction (p-value?<?0.05) in the number of aberrant crypt (AC) and aberrant crypt foci (ACF) at both administered doses. However, significant association (p-value?>?0.05) was not observed in reducing crypt multiplicity. The docking process resulted in estimated binding energies [-6.83 kcal/mol to -7.9 kcal/mol] which are closer to the positive controls or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [-4.55 kcal/mol to -10.84 kcal/mol]. The phytochemical-COX-2 interaction indicated the involvement of key amino acid residues in inhibition of cyclooxygenase like ARG120, TYR355, TYR385, SER530 and GLY526.Rumex abyssinicus had demonstrated a chemopreventive potential at post-initiation stage. As the virtual screening data suggested, COX-2 inhibition by the anthraquinones in the extract could be one mechanism for the observed chemopreventive effect.

Project description:BACKGROUND:Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the gene expression in kidneys from chronically exposed male F344 rats was investigated. METHODS:Male F344 rats were exposed to KBrO3 in drinking water for 52 and 100 wk. Kidneys were removed, frozen, and stored at -80°C, then used for Affymetrix microarray analysis. Gene expression patterns were examined using a non-carcinogenic (20 ppm) and carcinogenic dose (400 ppm) at 52 wk, and compared to 100 wk high dose (400 ppm) and adenoma gene expression. RESULTS:Statistical analysis revealed 144, 224, 43, and 994 genes out of 15866 from the 52 wk low, 52 wk high, 100 wk high, and adenomas respectively, were differentially expressed when compared to control kidneys. Gene ontology classification of the 52 wk high dose showed alterations of gene transcripts involved in oxidative stress, lipid metabolism, kidney function/ion transport, and cellular function. In a comparison of kidney development gene expression, alterations were seen in the adenomas but not in the 52 wk bromate-treated kidneys. However, the normal kidney from the high dose group resembled the adenoma expression pattern with early kidney development genes being up-regulated and adult phase genes being down-regulated. Moreover, eight genes were identified which could serve as biomarkers of carcinogenic exposure to bromate. The most promising of these was Pendrin, or Slc26a4, a solute carrier of chloride and iodide active in the kidney, thyroid, and inner ear. All these tissues are targets of KBrO3 toxicity. Expression array results were verified with quantitative real-time rtPCR. CONCLUSIONS:These data demonstrate that the 400 ppm carcinogenic dose of KBrO3 showed marked gene expression differences from the 20 ppm non-carcinogenic dose. Comparison of kidney development gene expression showed that the adenoma patterns were more characteristic of embryonic than adult kidneys, and that the normal kidney from the high dose group resembled the adenoma-like gene expression pattern. Taken together, the analysis from this study identifies potential biomarkers of exposure and illuminates a possible carcinogenic mode of action for KBrO3.

Dataset Information

The influence of chronic L-carnitine supplementation on the formation of preneoplastic and atherosclerotic lesions in the colon and aorta of male F344 rats.

Publications

The influence of chronic L-carnitine supplementation on the formation of preneoplastic and atherosclerotic lesions in the colon and aorta of male F344 rats.

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