Biomaterial Database

Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes. 1985

R A Mills, and C D Millis, and G A Dannan, and F P Guengerich, and S D Aust

The in vitro metabolism of polybrominated biphenyl (PBB) congeners by cytochrome P-450-dependent monooxygenases was investigated using hepatic microsomes isolated from immature male rats pretreated with 3-methylcholanthrene (MC) or phenobarbital (PB). MC pretreatment increased the NADPH-dependent microsomal metabolism of pure PBB congeners which possessed adjacent nonhalogenated ortho and meta carbons on at least one ring. 4,4'-Dibromobiphenyl (-DBB) was metabolized at the fastest rate, followed by 3,4,4'-tribromobiphenyl, 3,4,3',4'-tetrabromobiphenyl (-TBB), 2,3,3',4'-TBB, 2,5,3',4'-TBB, and 2,4,2',5'-TBB in decreasing order. It appeared that further bromination prevented metabolism since 2,4,5,3',4'-pentabromobiphenyl (-PBB), 2,3,4,2',4',5'-hexabromobiphenyl (-HBB), and 2,3,4,5,3'.4'-HBB were not metabolized although they possess adjacent nonhalogenated ortho and meta carbons. PB pretreatment increased in vitro rat hepatic microsomal metabolism of PBB congeners which possessed adjacent nonhalogenated meta and para carbons on at least one ring. 2,2'-DBB was metabolized at the fastest rate, followed by 2,4,2',5'-TBB, 2,5,2',5'-TBB, 2,3,3',4'-TBB, 2,5,3',4'-TBB, and 2,4,5,2',5'-PBB in decreasing order. The results suggest that the rates of metabolism of PBB congeners are dependent upon the positions of bromine and the form of cytochrome P-450 induced. In vitro rates of metabolism of 3,4,3',4'-TBB using hepatic microsomes isolated from rats pretreated with either 3,4,5,3',4',5'-HBB or 3,4,3',4'-TBB were also investigated. There was good correlation between the rates of 3,4,3',4'-TBB metabolism, induction of microsomal ethoxyresorufin-O-deethylase activity, and specific content of MC-inducible cytochrome P-450 (P-450 beta NF-B). The results suggest that the isozyme P-450 beta NF-B is responsible for the metabolism of 3,4,3',4'-TBB.

UI	MeSH Term	Description	Entries
D007527	Isoenzymes	Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.	Alloenzyme,Allozyme,Isoenzyme,Isozyme,Isozymes,Alloenzymes,Allozymes
D008297	Male		Males
D008748	Methylcholanthrene	A carcinogen that is often used in experimental cancer studies.	20-Methylcholanthrene,3-Methylcholanthrene,20 Methylcholanthrene,3 Methylcholanthrene
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
D010088	Oxidoreductases	The class of all enzymes catalyzing oxidoreduction reactions. The substrate that is oxidized is regarded as a hydrogen donor. The systematic name is based on donor:acceptor oxidoreductase. The recommended name will be dehydrogenase, wherever this is possible; as an alternative, reductase can be used. Oxidase is only used in cases where O2 is the acceptor. (Enzyme Nomenclature, 1992, p9)	Dehydrogenases,Oxidases,Oxidoreductase,Reductases,Dehydrogenase,Oxidase,Reductase
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
D011075	Polybrominated Biphenyls	Biphenyl compounds which are extensively brominated. Many of these compounds are toxic environmental pollutants.	Polybromobiphenyl Compounds,Biphenyls, Polybrominated,Compounds, Polybromobiphenyl
D011078	Polychlorinated Biphenyls	Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants.	PCBs,Polychlorinated Biphenyl,Polychlorobiphenyl Compounds,Biphenyl, Polychlorinated,Biphenyls, Polychlorinated,Compounds, Polychlorobiphenyl
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
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