Identification and induction of cytochromes P450, P450IIE1 and P450IA1 in rabbit bone marrow.
A number of drugs and xenobiotics which require metabolic activation to reactive metabolites by cytochrome P450 are toxic to hemopoietic tissue. In the present study we used immunoblot analysis and specific catalytic activities to identify two isozymes of cytochrome P450 (P450IIE1 and P450IA1) in rabbit bone marrow microsomal preparations. P450IIB1, P450IIC1, P450IIIA6 and P450IA2 were below detectable levels using immunoblot analysis. P450IIE1 was present at a concentration of 0.0065 nmol/mg of microsomal protein in marrow microsomes from untreated rabbits, and it was induced 12.9-fold by acetone treatment. The change in the P450IIE1 apoprotein determined immunochemically in bone marrow microsomes after acetone treatment was paralleled by a 9.4-fold increase in benzene hydroxylation, a P450IIE1-dependent activity. Aroclor 1254 pretreatment induced P450IA1 in marrow microsomes 11-fold to a specific content of about 0.025 nmol/mg of microsomal protein. 7-Ethoxyresorufin deethylation, a P450IA1-dependent activity, was induced 15.7-fold by Aroclor 1254 treatment. The increases in the enzymic activities are consistent with an increase in catalytically competent holoenzymes. The presence of these two isozymes in bone marrow could result in the metabolic activation of compounds in the bone marrow producing toxic metabolites at the site of toxicity.
Schnier
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Department of Environmental Health Sciences, School of Medicine, Case Western Reserve University, Cleveland OH 44106.
Laethem
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Koop
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D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001853:Bone Marrow / Q000201:enzymology*; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000096:biosynthesis; D004790:Enzyme Induction; D015151:Immunoblotting; D007527:Isoenzymes / Q000032:analysis*; D008099:Liver / Q000201:enzymology; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis; D011817:Rabbits
D001140:Aroclors; D007527:Isoenzymes; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase