Metabolic activation of carbon tetrachloride: induction of cytochrome P-450 with phenobarbital or 3-methylcholanthrene and its effect on covalent binding

Chemico-biological Interactions
H FrankH Remmer

Abstract

Anaerobic incubation of [14C]carbon tetrachloride with normal rat liver microsomes and microsomes from rats treated with the inducers phenobarbital (PB) and 3-methylcholanthrene (MC) reveals distinct differences in metabolic activation. While the increase in CO-binding pigment is comparable for both inducers, metabolism of CC14 is enhanced only by PB-induction; MC-induced microsomes are equivalent to microsomes from untreated animals. Sodium dodecyl sulphate (SDS)-electrophoresis of microsomal proteins confirms the expected increase at 52 000 daltons (cytochrome P-450 PB) on PB-induction, at 56 000 daltons (cytochrome P-450MC) on MC-induction; after anaerobic incubation with [14C]CC14 the electrophoretic pattern is largely unchange. The highly reactive radical intermediates of CC14-metabolism should attack the closest possible partner. Most of protein-bound radioactivity is located in the mass range between 47 000 and 54 000 daltons, indicating that cytochrome P-450PB is the isoenzyme mainly responsible for CC14-activation; cytochrome P-450MC plays virtually no role in metabolic activation. The direct participation of NADPH-cytochrome P-450 reductase appears unlikely, since the specific binding to proteins in the corresponding ...Continue Reading

References

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Citations

Dec 1, 1985·Environmental Health Perspectives·K H CheesemanT F Slater
Nov 24, 2004·Drug Metabolism Reviews·Johannes G FilserGyörgy A Csanády
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Related Concepts

Anaerobiosis
Metazoa
Metabolic Biotransformation
Carbon Tetrachloride
Cytochrome P-450 Oxygenase
Enzyme Induction
Methylcholanthrene
Microsomes, Liver
Luminal
August Rats

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