The Hepatocellular Hypoxia Criteria:2’Nitroimidazole Effect on Hepatocyte Carbohydrate Metabolizing Enzymes

Abstract

AbstractAim: to understand the 2’-nitroimidazole induced hypoxia and liver cell interaction, we proposed a “Hapatocellular Hypoxia Criteria”. Hypothesis: The nitroimidazole induced metabolic energy loss and oxygen depletion (hypoxia) in liver cell mitochondria causes the phagocytosis. Based on it, ten control subjects with 2’-nitroimidazole therapy were studied for their carbohydrate metabolizing enzymes in serum and hepatocellular enzymes in liver biopsy tissues. Materials and Methods: Proven ten control subjects were studied for hypoxia by enzyme assays. The 2’nitroimidazole treated paired ten subjects were studied for hypoxia using enzyme assays and hepatocellular cytomorphology by electron microscopy. Results and Discussion: Out of ten subjects on 2’-nitroimidazole, nine showed elevated carbohydrate metabolizing and lysosomal enzyme levels in serum. The enzymes glucokinase (in 80% samples), aldolase (in 80% samples), phosphofructokinase (in 80% samples), malate dehydrogenase (in 75% samples), isocitrate dehydrogenase (ICDH) (in 60% patients) were elevated while succinate dehydrogenase and lactate dehydrogenase (LDH) levels remained unaltered. Lysosomal enzymes β-glucuronidase, alkaline phosphatase, acid phosphatase, showed enhanced levels in the serum samples. In control ten liver biopsies, the hepatocytes and Kupffer cell preparations showed altered enzyme levels. Hepatocytes showed lowered glucokinase (in 80%), LDH (in 80%), and higher content of aldolase (in 80%), pyruvate kinase (in 100%), malate dehydrogenase (in 80%), ICDH (in 80%), citrate dehydrogenase (in 70%), phosphogluconate dehydrogenase (in 80%). Kupffer cells showed higher enzyme levels of β-glucuroronidase (in 80%), leucine aminopeptidase (in 70%), acid phosphatase (in 80%) and aryl sulphatase (in 88%). In these 10 biopsy samples from subjects on 2’-nitronidazole clinical trial, the electron microscopy cytomorphology observations showed swollen bizarre mitochondria, proliferative endoplasmic reticulum, and anisonucleosis after 2’-Nitroimidazole effect in liver cell damage. Conclusion: The proposed “Hepatocellular Hypoxia Criteria” served to define origin of liver hypoxia and showed altered hepatic enzyme activities with active phagocytosis and cytotoxicity in subjects after 2’-nitroimidazole treatment. The study suggests the enzyme based evaluation of nitroimidazole induced hypoxia monitoring and treatment of hepatic tumors and infected liver.