Cytosolic acetylation of sulfamethazine decreases hepatic release of ketone bodies in vivo in fasting rats

The effect of sulfamethazine (SMZ) on ketogenesis was studied in this report. SMZ, a sulfonamide metabolized by cytosolic acetylation in liver, was intraperitoneally injected (2 mmol/kg) to ketamine-anesthetized, overnight-fasted rats. Ketogenesis was measured by the Fick principle from the trans-hepatic (A-V) gradients of acetoacetate (AcAc) and D-β-hydroxybutyrate (gbŌHB). Prior to SMZ injection, A-V gradient of ketone bodies (KB) (AcAc + β-OHB) was -1.38 mM, indicating release from the liver. After SMZ injection, the release of KB decreased rapidly, maintainngg at a level ∼50% less than controls throughout the 2-h experimental period. Plasma concentrations of AcAc and β-OHB also decreased. In contrast, plasma concentrations and trans-hepatic gradients of free fatty acids (FFA) were not significantly affected. Our results thus indicate that SMZ acetylation in liver mobilizes acetyl CoA from mitochondria. Decreased hepatic ketogenesis limits the availability of KB and may thus affect energy metabolism in the extra-hepatic hepatic tissues. The incomplete inhibition on ketogenesis may indicate compartmentation of acetyl CoA in liver mitochondria.