Cahill cycle

Because skeletal muscle is unable to utilize the urea cycle to safely dispose of ammonium ions generated in the breakdown of branch chain amino acids, it must get rid of it in a different way.

The alanine amino acid acts as a shuttle - it leaves the cell, entering the blood stream and traveling to hepatocytes in the liver, where essentially this entire process is reversed.

[9] Studies have demonstrated that the glucose-alanine cycle may play a direct role in regulation of hepatic (liver) mitochondrial oxidation, particularly during periods of extended fasting.

[9] To confirm whether or not the glucose-alanine cycle has a causal relationship with the observed effect, a secondary group of patients, also subjected to the same fasting conditions, were subsequently injected with a dose of L-alanine.

[12] The search for alternative treatment options remains a lucrative area of research as current available therapeutics (surgery, radiotherapy, chemotherapy) generally have severe side effects and/or low success rates with HCC.

[12] One common characteristic of many novel alternative and/or supplementary treatments is the targeting of cellular metabolism of cancer cells, due to their general hyper-metabolic state which favors rapid growth and proliferation.

[12] The researchers involved in this study speculated exogenous alanine, processed via the glucose-alanine cycle, to be one of the alternative energy sources for HCC cells in a nutrient deficient environment and that this dependency can be harnessed for targeted therapy.

[12] Next, they performed a series of over expression and loss of function experiments and determined that specifically Glutamic Pyruvate Transaminase 1 (GPT1) is the GPT isomer primarily involved in alanine turnover in HCC cells, consistent with previous findings that GPT1 tends to be found in the liver.

[12] Their study demonstrated that components of the glucose-alanine cycle, particularly GPT1, may be a good choice as a target for alternative HCC therapies and that Berberine, as a plant- derived selective GPT1 inhibitor, has potential for use in one of these novel medicines.