BCH

Glutamate dehydrogenase activator BCH stimulating reductive amination prevents high fat/high fructose diet-induced steatohepatitis and hyperglycemia in C57BL/6J mice.[Pubmed:27874078]

Sci Rep. 2016 Nov 22;5:37468.

Individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) induced by high calorie western diet are characterized by enhanced lipogenesis and gluconeogenesis in the liver. Stimulation of reductive amination may shift tricarboxylic acid cycle metabolism for lipogenesis and gluconeogenesis toward glutamate synthesis with increase of NAD+/NADH ratio and thus, ameliorate high calorie diet-induced fatty liver and hyperglycemia. Stimulation of reductive amination through glutamate dehydrogenase (GDH) activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) reduced both de novo lipogenesis and gluconeogenesis but increased the activities of sirtuins and AMP-activated kinase in primary hepatocytes. Long-term BCH treatment improved most metabolic alterations induced by high fat/high fructose (HF/HFr) diet in C57BL/6J mice. BCH prevented HF/HFr-induced fat accumulation and activation of stress/inflammation signals such as phospho-JNK, phospho-PERK, phospho-p38, and phospho-NFkappaB in liver tissues. Furthermore, BCH treatment reduced the expression levels of inflammatory cytokines such as TNF-alpha and IL-1beta in HF/HFr-fed mouse liver. BCH also reduced liver collagen and plasma levels of alanine transaminase and aspartate transaminase. On the other hand, BCH significantly improved fasting hyperglycemia and glucose tolerance in HF/HFr-fed mice. In conclusion, stimulation of reductive amination through GDH activation can be used as a strategy to prevent high calorie western diet-induced NAFLD and T2D.

BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells.[Pubmed:18520037]

Biol Pharm Bull. 2008 Jun;31(6):1096-100.

PURPOSE: L-Type amino acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. METHODS: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using amino acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. RESULTS: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. CONCLUSION: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral amino acids necessary for cancer cell growth.

L-type amino acid transporter-1 overexpression and melphalan sensitivity in Barrett's adenocarcinoma.[Pubmed:15068672]

Neoplasia. 2004 Jan-Feb;6(1):74-84.

The L-type amino acid transporter-1 (LAT-1) has been associated with tumor growth. Using cDNA microarrays, overexpression of LAT-1 was found in 87.5% (7/8) of esophageal adenocarcinomas relative to 12 Barrett's samples (33% metaplasia and 66% dysplasia) and was confirmed in 100% (28/28) of Barrett's adenocarcinomas by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed LAT-1 staining in 37.5% (24/64) of esophageal adenocarcinomas on tissue microarray. LAT-1 also transports the amino acid-related chemotherapeutic agent, melphalan. Two esophageal adenocarcinoma and one esophageal squamous cell line, expressing LAT-1 on Western blot analysis, were sensitive to therapeutic doses of melphalan (P <.001). Simultaneous treatment with the competitive inhibitor, BCH [2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid], decreased sensitivity to melphalan (P <.05). In addition, confluent esophageal squamous cultures were less sensitive to melphalan (P <.001) and had a decrease in LAT-1 protein expression. Tumors from two esophageal adenocarcinoma cell lines grown in nude mice retained LAT-1 mRNA expression. These results demonstrate that LAT-1 is highly expressed in a subset of esophageal adenocarcinomas and that Barrett's adenocarcinoma cell lines expressing LAT-1 are sensitive to melphalan. LAT-1 expression is also retained in cell lines grown in nude mice providing a model to evaluate melphalan as a chemotherapeutic agent against esophageal adenocarcinomas expressing LAT-1.

L-type amino acid transporters in two intestinal epithelial cell lines function as exchangers with neutral amino acids.[Pubmed:11925469]

J Nutr. 2002 Apr;132(4):733-8.

The present study examined the functional characteristics of the inward [(14)C]-L-leucine transporter in two intestinal epithelial cell lines (human Caco-2 and rat IEC-6). The uptake of [(14)C]-L-leucine was largely promoted through an energy-dependent and sodium-insensitive transporter, although a minor component of [(14)C]-L-leucine uptake ( approximately 15%) required extracellular sodium. [(14)C] -L-leucine uptake was insensitive to N-(methylamino)-isobutyric acid, but competitively inhibited by 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BCH). Both L- and D-neutral amino acids, but not acidic and basic amino acids, markedly inhibited [(14)C]-L-leucine accumulation. The efflux of [(14)C]-L-leucine was markedly increased (P < 0.05) by L-leucine and BCH, but not by L-arginine. In IEC-6 cells, but not in Caco-2 cells, the uptake of [(14)C]-L-leucine at acidic pH (5.0 and 5.4) was greater (P < 0.05) than at pH 7.4. In conclusion, it is likely that system B(0) might be responsible for the sodium-dependent uptake of L-leucine in Caco-2 and IEC-6 cells, whereas sodium-independent uptake of L-leucine may include system LAT1, whose activation results in transstimulation of L-leucine outward transfer.

LAT1-IN-1 (BCH) is a selective and competitive inhibitor of large neutral amino acid transporter 1 (LAT1) significantly inhibit cellular uptake of amino acids and mTOR phosphorylation, which induces the suppression of cancer growth and apoptosis.

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