In a recent study in rats, alanine aminotransferase (ALT), the preferred plasma
biomarker of hepatocellular injury in rats, was ineffective at detecting marked
hepatic necrosis produced by acetaminophen (Human and Experimental
Toxicology 19, 277-83, 2000). In contrast, glutamate dehydrogenase (GLDH)
was markedly elevated. Accordingly, these enzymes were comprehensively evaluated as
plasma biomarkers of hepatocellular injury in rats using several other models of
hepatic injury, including partial hepatectomy and exposure to methapyrilene,
dexamethasone, cyproterone, isoniazid, lead nitrate, and Wyeth-14643. Other enzymes
also evaluated were aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH),
and the hepatobiliary marker alkaline phosphatase (ALP). Compared to plasma ALT
increases, plasma GLDH increases were up to 10-fold greater, up to 3-fold more
persistent, and occurred at times following hepatocellular injury when plasma ALT was
not increased. Plasma GLDH activity was not inhibited by the test compounds, whereas
ALT was substantially inhibited by both isoniazid and lead nitrate. While plasma GLDH
activity was unaffected by induction, ALT was induced by cyproterone and
dexamethasone, and ALP was induced by Wyeth-14643 and partial hepatectomy. GLDH was
concluded to be a more effective biomarker of acute hepatic injury than ALT, AST, SDH
or ALP in the rat, based primarily on the large increase following hepatocellular
injury, prolonged persistence in the blood following injury, high sensitivity for
detection of injury (including pre-necrotic injury), high tissue specificity, and
lower susceptibility to inhibition or induction.
