ASCORBIC ACID SYNTHESIS IN NORMAL AND DRUG-TREATED RATS, STUDIED WITH l-ASCORBIC-1-C14 ACID

Burns, J. J.; Mosbach, Erwin H.; Schulenberg, Shirley

doi:10.1016/s0021-9258(18)65685-6

Cited by 77 publications

(1 citation statement)

References 12 publications

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“…This suggests that other major physiological processes of AA elimination exist in the calf. In the rat, urinary excretion accounts for ϳ15% of the AA synthesized daily under normal physiological conditions (9). In the guinea pig, only 8% of the label was recovered in urine, demonstrating that under physiological conditions the excretion of AA and its metabolites in the urine is not an important route of elimination (8).…”

Section: Discussionmentioning

confidence: 99%

Ascorbic acid disposition kinetics in the plasma and tissues of calves

Toutain

Béchu

Hidiroglou

1997

American Journal of Physiology-Regulatory, Integrative and Comp

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Kinetic plasma disposition parameters and tissue distribution of ascorbic acid (AA) and dihydroascorbic acid (DHA) were determined in newborn calves. After a radiolabeled AA intravenous administration, the plasma clearance (Cl) was low (40.8 ± 9.5 ml ⋅ kg−1 ⋅ h−1), the steady-state volume of distribution (Vss) was very high (8.9 ± 2.2 l/kg), and the AA mean residence time (MRT) was long (230 ± 85 h). After administration of a 3-g dose of AA, the Cl was high (450 ± 146 ml ⋅ kg−1 ⋅ h−1), the Vss was low (0.658 ± 0.236 l/kg), and the MRT was short (1.49 ± 0.41 h), indicating a strong nonlinearity of AA disposition in calves and the impossibility of preventing scurvy with the use of a loading AA dose. Nonlinearity was explained by the saturation of both kidney reabsorption and tissue uptake. The estimated AA body pool size was 23.1 ± 6.8 mg/kg. On the basis of a compartmental analysis and actual tissue concentration measurements, it is suggested that the lung (19% of the pool) constitutes a low-capacity but rapidly mobilized pool able to cover an acute need for AA, whereas muscle and liver (40 and 33% of the pool, respectively) are high-capacity AA pools, but slowly mobilized and involved in covering the calf’s long-term AA requirements. The average daily AA entry rate over the first 7 days of life was 3.43 ± 1.16 mg/kg, and it is suggested that the calf is able to synthesize AA at an early stage.

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Section: Discussionmentioning

confidence: 99%

Ascorbic acid disposition kinetics in the plasma and tissues of calves

Toutain

Béchu

Hidiroglou

1997

American Journal of Physiology-Regulatory, Integrative and Comp

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Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo^−/− mice

et al. 2014

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Hypoxia-inducible factor-1 (HIF-1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment-resistant tumor phenotype. HIF-1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF-1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57BL/6 Gulo−/− mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16-F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild-type ascorbate levels led to a reduction in growth of B16-F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF-1α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF-1 target proteins CA-IX, GLUT-1, and VEGF in both B16-F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16-F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF-1 pathway activity.

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Diet composition as a source of variation in experimental animal models of cancer cachexia

Giles

Chen

Jagoe

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundA variety of experimental animal models are used extensively to study mechanisms underlying cancer cachexia, and to identify potential treatments. The important potential confounding effect of dietary composition and intake used in many preclinical studies of cancer cachexia is frequently overlooked. Dietary designs applied in experimental studies should maximize the applicability to human cancer cachexia, meeting the essential requirements of the species used in the study, matched between treatment and control groups as well as also being generally similar to human consumption.MethodsA literature review of scientific studies using animal models of cancer and cancer cachexia with dietary interventions was performed. Studies that investigated interventions using lipid sources were selected as the focus of discussion.ResultsThe search revealed a number of nutrient intervention studies (n = 44), with the majority including n‐3 fatty acids (n = 16), mainly eicosapentaenoic acid and/or docosahexaenoic acid. A review of the literature revealed that the majority of studies do not provide information about dietary design; food intake or pair‐feeding is rarely reported. Further, there is a lack of standardization in dietary design, content, source, and overall composition in animal models of cancer cachexia. A model is proposed with the intent of guiding dietary design in preclinical studies to enable comparisons of dietary treatments within the same study, translation across different study designs, as well as application to human nutrient intakes.ConclusionThe potential for experimental endpoints to be affected by variations in food intake, macronutrient content, and diet composition is likely. Diet content and composition should be reported, and food intake assessed. Minimum standards for diet definition in cachexia studies would improve reproducibility of pre‐clinical studies and aid the interpretation and translation of results to humans with cancer.

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ASCORBIC ACID SYNTHESIS IN NORMAL AND DRUG-TREATED RATS, STUDIED WITH l-ASCORBIC-1-C14 ACID

Cited by 77 publications

References 12 publications

Ascorbic acid disposition kinetics in the plasma and tissues of calves

Ascorbic acid disposition kinetics in the plasma and tissues of calves

Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo^−/− mice

Diet composition as a source of variation in experimental animal models of cancer cachexia

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ASCORBIC ACID SYNTHESIS IN NORMAL AND DRUG-TREATED RATS, STUDIED WITH l-ASCORBIC-1-C14 ACID

Cited by 77 publications

References 12 publications

Ascorbic acid disposition kinetics in the plasma and tissues of calves

Ascorbic acid disposition kinetics in the plasma and tissues of calves

Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo−/− mice

Diet composition as a source of variation in experimental animal models of cancer cachexia

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Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo^−/− mice