Advantages of glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats.
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.
O'Brien
P J
PJ
Safety Assessment, GlaxoSmithKline, Park Road, Ware SG12 0DP, UK.
Slaughter
Mark R
MR
Polley
S R
SR
Kramer
K
K
D000208:Acute Disease; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000201:enzymology* / Q000473:pathology; D003534:Cyproterone / Q000633:toxicity; D003907:Dexamethasone / Q000633:toxicity; D005969:Glutamate Dehydrogenase / Q000097:blood*; D006498:Hepatectomy; D007538:Isoniazid / Q000633:toxicity; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D007854:Lead / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008701:Methapyrilene / Q000633:toxicity; D009566:Nitrates / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity
D015415:Biomarkers; D009566:Nitrates; D011743:Pyrimidines; D007854:Lead; C017461:lead nitrate; D003907:Dexamethasone; C006253:pirinixic acid; D008701:Methapyrilene; D003534:Cyproterone; D007064:L-Iditol 2-Dehydrogenase; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D007538:Isoniazid