Changes in the antioxidant defense and hepatic drug metabolizing enzyme and isoenzyme levels, 8-hydroxydeoxyguanosine formation and expressions of c-raf.1 and insulin-like growth factor II genes during the stages of development of hepatocellular carcinoma in rats.
This is an extensive study in a defined initiation-promotion hepatocellular carcinoma model of hepatocarcinogenesis (in rats) in which many important marker enzymes and isoenzymes and 8-hydroxydeoxyguanosine formation have been studied together with two very important cellular proliferating genes, insulin-like growth factor II and c-raf.1, known for their role in hepatocellular cancer development. Experiments were carried out on hepatic tissues of male Sprague-Dawley rats. Variations in different enzyme/isoenzyme activities/contents/expression pattern and 8-hydroxydeoxyguanosine-positive cells were studied. Insulin-like growth factor II and c-raf.1 gene expressions were monitored. A direct shift with increase in size and numbers of lesions was found to occur in different experimental groups. In this study, glutathione peroxidase (1.14 and 1.46-fold) and reduced triphosphopyridine nucleotide (TPNH)-cytochrome-c-reductase (1.94 and 2.94-fold) activities, cytochrome b5 (1.57 and 3.28-fold) and P-450 contents (1.45 and 1.22-fold), glutathione content (1.27 and 1.45-fold) and superoxide dismutase and catalase (1.16 and 1.39-fold) activities in group A animals were found to be lower than those in initiation and promotion studies, respectively. 8-Hydroxydeoxyguanosine-positive nuclei count showed that oxidative damage of nuclear DNA enhanced with the progress of the disease. The insulin-like growth factor II expression was found to be predominant in hepatocellular carcinoma and in early preneoplastic lesions. Unlike insulin-like growth factor II, c-raf.1 expression was located in the late basophilic lesions associated with hepatocellular carcinoma. During the various stages of the development of hepatocellular carcinoma, the enzymes played a significant role in metabolizing carcinogens and thereby scavenging various toxic metabolites or free radicals produced. A sequence of cellular changes starting from the appearance of glycogen storage foci to basophilic foci leading to hepatocellular carcinoma via mixed cell foci varied the activity/content or expression pattern of the enzymes and isoenzymes and in 8-hydroxydeoxyguanosine formation. It has been established that c-raf.1-induced signaling pathways activated by insulin-like growth factor II is implicated in the late stage of development of cancer.
Mukherjee
Biswajit
B
Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India. biswajit55@yahoo.com
Das
Tanushree
T
Ghosh
Shampa
S
Datta
Subrata
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008658:Inactivation, Metabolic; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D007527:Isoenzymes; D007335:Insulin-Like Growth Factor II; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019908:Proto-Oncogene Proteins c-raf; D005952:Glucose-6-Phosphatase; D003849:Deoxyguanosine; D005978:Glutathione