Identification and induction of cytochrome P450 2E1 in rat Kupffer cells.
Kupffer cells, the resident macrophages of the liver, have a well characterized role in the removal of blood-born foreign substances by phagocytosis. Because Kupffer cells may contribute to hepatic xenobiotic metabolism, the current studies evaluated the presence and inducibility of P450 2E1 in rat Kupffer cells. Hepatocytes and Kupffer cells were isolated from the livers of control and acetone-treated (1% v/v acetone in the drinking water for 7 days) rats. P450 2E1 was immunochemically detectable at low levels in Kupffer cell homogenates from untreated rats and was induced greater than 10-fold by acetone-treatment. The presence of P450 2E1 in Kupffer cells from untreated rats was confirmed by inhibition of benzene hydroxylation with anti-P450 2E1 immunoglobulin G. Benzene hydroxylase activity was induced 16.3-fold in Kupffer cells isolated from acetone-treated rats and remained 70% inhibitable by anti-P450 2E1 antibody. The benzene hydroxylase activity of hepatocytes from the same animals was induced 3.9-fold by acetone treatment. The specific activity for benzene hydroxylation of Kupffer cell homogenates from acetone-treated rats was nearly equal to that for the hepatocytes from the same animals. The presence and inducibility of P450 2E1 in Kupffer cells suggests that, under conditions where P450 2E1 is induced, Kupffer cell-generated metabolites may contribute to Kupffer cell toxicity, as well as general hepatic injury.
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Department of Environmental Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Chernosky
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D000096:Acetone / Q000494:pharmacology; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction; D015151:Immunoblotting; D007728:Kupffer Cells / Q000166:cytology / Q000201:enzymology*; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000096:Acetone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C019765:benzene 1,2-dioxygenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating