Which buffer is considered the principal buffer of intracellular fluids?

• A. Bicarbonate/carbonic acid
• B. Hemoglobin
• C. Plasma proteins
• D. Phosphate buffer system

Answer: (D)

The main idea is how buffering capacity is distributed between compartments. Inside cells, the phosphate buffering system is best suited to maintain the cytosolic pH because its components, dihydrogen phosphate and hydrogen phosphate, are present at high intracellular concentrations and have a pKa around 6.8, which sits right near the normal intracellular pH. This makes the H2PO4–/HPO4^2– couple highly effective at resisting pH changes around neutral pH: when acid is added, HPO4^2– accepts a proton to form H2PO4–, and when base is added, H2PO4– donates a proton to form HPO4^2–. The buffering response is most efficient when the pH is close to the pKa, so this system readily stabilizes intracellular pH.

Bicarbonate/carbonic acid is the principal buffer of extracellular fluids (plasma and interstitial fluid) because CO2 diffuses and equilibrates with bicarbonate in those compartments, providing strong extracellular buffering. Hemoglobin and plasma proteins do contribute to buffering, including within cells, but they are not the dominant intracellular buffer; phosphate plays the central role in the cytosol.