Biomaterial Database

Hepatic microsomal warfarin metabolism in warfarin-resistant and susceptible mouse strains: influence of pretreatment with cytochrome P-450 inducers. 1990

F A Sutcliffe, and A D MacNicoll, and G G Gibson

Department of Biochemistry, University of Surrey, Guildford, U.K.

In the present paper, the heterogeneity of hepatic cytochrome P-450 isoenzymes in the mouse has been probed, using warfarin as the substrate. Both sex and strain differences in the in vitro microsomal metabolism of warfarin have been investigated in male and female warfarin-resistant HC and warfarin-susceptible LAC-grey mouse strains. Animals were either untreated or treated with the cytochrome P-450 inducers phenobarbitone, beta-napthoflavone or clofibrate. In both sexes and strains of mice, metabolism of warfarin was stereoselective in favour of the R(+) enantiomer. However, regioselectively was different in both strains and sexes of untreated animals. After pretreatment with phenobarbitone, increases in the rate of formation of 4' and 7-hydroxy R(+) and S(-) warfarin metabolites in HC mice were observed, compared with untreated animals. In LAC-grey mice increases in 4'-, 6-, 7- and 8-hydroxy R(+) and S(-) warfarin metabolites were noted, compared with untreated animals. This data indicated that different amounts or forms of cytochrome P-450s were responsible for warfarin metabolism after phenobarbitone treatment in the two strains. Pretreatment of animals with beta-napthoflavone resulted in significant decreases in the rat of R(+) warfarin metabolism in both strains and sexes of mice indicating that the beta-naphthoflavone-inducible cytochrome P-450 isoenzymes were less active in the metabolism of warfarin, as compared to the uninduced isoenzymes. In addition, the cytochrome P-450 isoenzyme composition in the two mouse strains was different after clofibrate pretreatment, as reflected in reduced levels of some warfarin metabolites and a reduced total metabolism of warfarin, consistent with the narrow substrate specificity of clofibrate-induced cytochrome P450IVA1 for fatty acid hydroxylation. Accordingly, it is clear that both the basal and xenobiotic inducible hepatic cytochrome P-450 isoenzymes in warfarin-resistant and susceptible mice are different and therefore have implications for the in vivo disposition of warfarin.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D008862	Microsomes, Liver	Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough.	Liver Microsomes,Liver Microsome,Microsome, Liver
D010634	Phenobarbital	A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.	Phenemal,Phenobarbitone,Phenylbarbital,Gardenal,Hysteps,Luminal,Phenobarbital Sodium,Phenobarbital, Monosodium Salt,Phenylethylbarbituric Acid,Acid, Phenylethylbarbituric,Monosodium Salt Phenobarbital,Sodium, Phenobarbital
D002994	Clofibrate	A fibric acid derivative used in the treatment of HYPERLIPOPROTEINEMIA TYPE III and severe HYPERTRIGLYCERIDEMIA. (From Martindale, The Extra Pharmacopoeia, 30th ed, p986)	Athromidin,Atromid,Atromid S,Clofibric Acid, Ethyl Ester,Ethyl Chlorophenoxyisobutyrate,Miscleron,Miskleron,Chlorophenoxyisobutyrate, Ethyl
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug
D004790	Enzyme Induction	An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.	Induction, Enzyme
D005260	Female		Females
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001571	Benzoflavones	Organic compounds containing a BENZENE ring attached to a flavone group. Some of these are potent arylhydrocarbon hydroxylase inhibitors. They may also inhibit the binding of NUCLEIC ACIDS to BENZOPYRENES and related compounds. The designation includes all isomers; the 7,8-isomer is most frequently encountered.	Benzoflavone Compounds,Compounds, Benzoflavone