ABSTRACT
L-3-Aminoisobutyric acid (L-BAIBA) is an endogenous compound in human metabolism when thymine and valine undergo catabolism. L-BAIBA represents one of the two isomers of BAIBA in biological systems. BAIBA has been shown to reduce body fat percentage via an increase in fatty acid oxidation and a decrease in hepatic lipogenesis. However, no toxicological effects of L-BAIBA in animals or humans have been established. The present study was designed to evaluate the safety and toxic potentials of this compound, where L-BAIBA was administered orally to Sprague Dawley rats at 100, 300, and 900 mg/kg/day for 90 days. No treatment-related adverse effects were observed in any of the treatment groups. Based on the results, the No-Observed-Adverse-Effect Level (NOAEL) of L-BAIBA was 900 mg/kg/day.
Subject(s)
Aminoisobutyric Acids , Lipid Metabolism , Amino Acid Metabolism, Inborn Errors , Aminoisobutyric Acids/metabolism , Aminoisobutyric Acids/toxicity , Aminoisobutyric Acids/urine , Animals , Humans , Rats , Rats, Sprague-DawleyABSTRACT
Alpha-aminoisobutyric acid (AIB), or alpha-methyl alanine, is a nonmetabolized amino acid transported into cells, particularly malignant cells, predominantly by the 'A' amino acid transport system. Since it is not metabolized, [1-11C]-AIB can be used to quantify A-type amino acid transport into cells using a relatively simple compartmental model and quantitative imaging procedures (e.g. positron tomography). The tissue distribution of [1-11C]-AIB was determined in six dogs bearing spontaneous tumors, including lymphosarcoma, osteogenic sarcoma, mammary carcinoma, and adenocarcinoma. Quantitative imaging with tissue radioassay confirmation at necropsy showed poor to excellent tumor localization. However, in all cases the concentrations achieved appear adequate for amino acid transport measurement at known tumor locations. The observed low normal brain (due to blood-brain barrier exclusion) and high (relative to brain) tumor concentrations of [1-11C]-AIB suggest that this agent may prove effective for the early detection of human brain tumors.
Subject(s)
Amino Acids/metabolism , Aminoisobutyric Acids , Carbon Radioisotopes , Neoplasms, Experimental/diagnostic imaging , Aminoisobutyric Acids/metabolism , Aminoisobutyric Acids/toxicity , Animals , Body Burden , Carbon Radioisotopes/adverse effects , Carbon Radioisotopes/metabolism , Dogs , Female , Male , Metabolic Clearance Rate , Mice , Radionuclide Imaging , Tissue DistributionABSTRACT
It was found that differentiation of murine erythroleukemia cells can be induced by 5-fluorodeoxyuridine (FudR), amethopterin and alpha-aminoisobutyrate. Each of these compounds is believed to delay the onset of DNA synthesis. Since relief of the FudR block to DNA synthesis by addition of thymidine can increase the number of initiation sites for replication (Taylor, 1977), the effect of various inducers and inhibitors of differentiation of Friend cells upon the relative number of initiation sites for replication and transcription was investigated. Very efficient inducers of hemoglobin synthesis, hexamethylene bisacetamide (HMBA) and dimethylsulfoxide (DMSO), increase the number of initiation sites for transcription and HMBA also increases the number of functional initiation sites for replication. Two other compounds that induce differentiation of Friend cells, low levels of actinomycin D and FudR, did not increase the number of initiation sites for transcription. Compounds that prevent induction of hemoglobin synthesis by HMBA and DMSO include 5-bromodeoxyuridine (BrdU) and novobiocin. Both of these compounds were found to decrease the number of functional initiation sites for transcription and it is known that both compounds reduce the number of initiation sites for replication. The relation between initiation of replication and transcription, and its effect upon differentiation of erythroleukemia cells is discussed.
Subject(s)
DNA Replication , Hemoglobins/biosynthesis , Leukemia, Experimental/physiopathology , Transcription, Genetic , Acetamides/pharmacology , Aminoisobutyric Acids/toxicity , Animals , Cell Differentiation , Cell Line , DNA Replication/drug effects , Dimethyl Sulfoxide/pharmacology , Floxuridine/toxicity , Hemoglobins/genetics , Kinetics , Methotrexate/toxicity , Mice , Transcription, Genetic/drug effectsABSTRACT
Mutants of Chinese hamster ovary cells (CHO-K1 Pro-), resistant to the proline transport antagonist 2-(methylamino)-isobutyrate (MeAIB) were isolated by a single-step procedure. Mutation rates to Pro+ and to Pro- MeAIB resistance (MeAIBr) are 1.7 X 10(-6) and 2.4 X 10(-5), respectively. Several Pro- MeAIBr mutants were tested by measuring the uptake of 0.05 mM proline through the various amino acid transport systems: some showed increases in one transport system only; others revealed pleiotropic changes affecting two or more systems; still others had no apparent change in proline transport. One Pro- MeAIBr mutant analyzed in detail (MeAIBr22) was isolated after EMS treatment as resistant to 5 mM MeAIB, is Pro-, stable, and shows a 1.6-fold increase in the initial velocity of transport of 0.05 mM proline. There appears to be no change in the velocity of proline transport through the amino acid transport systems A, P, and L, and the "glutamine inhibitable fraction." In contrast, there is a 5.5-fold increase in the velocity of transport of 0.05 mM proline through the ASC system. Kinetic studies reveal a sixfold increase in the Vm and a slight increase in the Km of the transport of serine through the ASC system. Hybrids between MeAIBr22 and CHO-K1 Pro-, OUAr, HPRT- showed the parental phenotype. These results indicate that the mutant ASC phenotype of MeAIBr22 is recessive and is probably the result of a regulatory gene mutation.
Subject(s)
Aminoisobutyric Acids/toxicity , Genes, Recessive , Mutation , Animals , Biological Transport/drug effects , Cell Line , Clone Cells , Cricetinae , Cricetulus , Drug Resistance , Ethyl Methanesulfonate/toxicity , Female , Kinetics , Ovary , Proline/metabolism , Serine/metabolismABSTRACT
A reliable method for the determination of beta-aminoisobutyric acid in serum was developed utilizing an automated amino acid analyzer. The serum concentrations of beta-aminoisobutyric acid were determined in 20 normal subjects and in 71 uremic patients. The mean serum level of beta-aminoisobutyric acid was markedly increased in the uremic patients to 0.856 +/- 0.910 (mean +/- SD) mg/100 ml as compared with a normal value of 0.026 +/- 0.027 mg/100 ml. The distribution of serum beta-aminoisobutyric acid level in uremic patients was wide-spread, and there was no correlation between the serum levels of the amino acid and those of urea nitrogen, creatinine and uric acid. The toxicity of beta-aminoisobutyric acid on mice with acute renal failure induced by uranyl acetate was investigated and compared with that of alpha-amino-n-butyric acid and gamma-amino-n-butyric acid. All mice given more than 4 g/kg body wt of beta-aminoisobutyric acid showed twitching and cramps, and some of them died. However, the control mice given an equivalent dose of alpha-amino-n-butyric acid or gamma-amino-n-butyric acid showed no change. These results suggest that beta-aminoisobutyric acid might be a factor influencing the development and progression of uremic toxemia.
