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Induction of cytochrome P-450 isozymes by mirex and chlordecone
M Lewandowski1, P Levi, E Hodgson
1BASF Corporation, Agricultural Research Center, Research Triangle Park, North Carolina 27709.
Abstract:
The effect of the insecticides, mirex and chordecone (Kepone), on the cytochrome P-450 monooxygenase system in C57BL/6N mouse liver microsomes was studied. Mice were treated intraperitoneally with low (6 mg/kg) and high (30 mg/kg) doses of mirex and chlordecone in corn oil for 2 days. For comparison, mice were also treated with either phenobarbital (PB) or 3-methylcholanthrene (3-MC). All treatments significantly increased the hepatic microsomal P-450 content over that of controls. Benzphetamine N-demethylase, ethoxyresorufin O-deethylase, benzo[a]pyrene hydroxylase, and acetanilide hydroxylase activities were also determined. Mirex and chlordecone resembled phenobarbital with respect to the induction of monooxygenase activities. Immunoquantitation with antibodies to purified P-450 IIB1 (Pb-induced P-450) and P-450 IA1 (3-MC-induced P-450) indicated that mirex and chlordecone induced P-450 IIB1 in a dose-dependent manner. The high dose of mirex also induced a small amount of a protein cross reacting with the antibody to IA1. The induction of this isozyme did not, however, contribute significantly to the monooxygenase activities measured.
Insights
Mirex and chlordecone insecticides significantly increase cytochrome P-450 content in mouse liver microsomes. These compounds, similar to phenobarbital, induce specific P-450 isozymes, affecting monooxygenase activities.
Area of Science:
- Toxicology
- Biochemistry
- Pharmacology
Background:
- Cytochrome P-450 monooxygenase system plays a crucial role in xenobiotic metabolism.
- Insecticides like mirex and chlordecone can interfere with this system.
- Understanding their effects is vital for assessing toxicological risks.
Purpose of the Study:
- To investigate the impact of mirex and chlordecone on the cytochrome P-450 monooxygenase system in C57BL/6N mouse liver microsomes.
- To compare the effects of these insecticides with known P-450 inducers, phenobarbital and 3-methylcholanthrene.
Main Methods:
- Mice were administered intraperitoneal injections of mirex and chlordecone at low (6 mg/kg) and high (30 mg/kg) doses for 2 days.
- Hepatic microsomal P-450 content and specific monooxygenase activities (e.g., benzphetamine N-demethylase) were measured.
- Immunoquantitation was used to determine the induction of specific P-450 isozymes (P-450 IIB1 and P-450 IA1).
Main Results:
- Both mirex and chlordecone significantly increased hepatic microsomal P-450 content compared to controls.
- These insecticides induced monooxygenase activities similarly to phenobarbital.
- Mirex and chlordecone dose-dependently induced P-450 IIB1; mirex also induced a minor amount of P-450 IA1.
Conclusions:
- Mirex and chlordecone are inducers of the cytochrome P-450 monooxygenase system in mouse liver.
- Their induction profile resembles that of phenobarbital, primarily affecting P-450 IIB1.
- While a minor induction of P-450 IA1 was observed with mirex, it did not significantly contribute to the measured monooxygenase activities.