The cerium-induced liver injury and oxidative drug metabolism in DBA/2 and C57BL/6 mice.
The influence of the known hepatotoxic agent, cerium (Ce) on the activity of liver microsomal monoxygenases, especially coumarin 7-hydroxylase (COH) was investigated in two inbred strains of male mice, DBA/2N and C57BL/6N. Ce was injected intravenously in three doses (0.5, 1.0 and 2.0 mg/kg body wt) and the animals were killed 24 or 72 h later. On the basis of histological assessment of the liver, C57BL/6N mice are apparently more resistant to the hepatotoxic effect of Ce. At 24 h, COH activity was increased in a dose-dependent manner in DBA/2 animals, whereas no change was seen in C57BL/6N animals. A significant increase in all other enzymes studied, cytochrome P-450 (P450), ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase, was seen in DBA/2 mice injected with the highest dose of Ce. At 72 h Ce increased CON activity, as well as other enzymes, in C57BL/6N mice in a dose-dependent manner, whereas in DBA/2 mice the increase was only seen after the two lower doses, the highest dose causing severe morphological changes in the liver structure and a clear decrease in COH and other activities. The distribution studies with Ce-141 showed that C57BL/6N livers contained more Ce than DBA/2 livers after the highest dose.
Department of Pharmacology and Toxicology, University of Oulu, Finland.
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Arvela
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Kraul
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Stenbäck
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Pelkonen
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002563:Cerium / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism
D002563:Cerium; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6