Biomaterial Database

Structure-dependent induction of CYP2B by polychlorinated biphenyl congeners in female Sprague-Dawley rats. 1995

K Connor, and S Safe, and C R Jefcoate, and M Larsen

Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.

The dose-response induction of hepatic microsomal pentoxyresorufin O-dealkylase (PROD) activity by phenobarbital (PB) and several polychlorinated biphenyl (PCB) mixtures and congeners was determined in the immature female Sprague-Dawley rat. At a dose of 75 mg/kg/day of PB for 3 days, the microsomal PROD activity was 2154 pmol/min/mg protein. Aroclors 1260, 1254, 1242, and 1016 did not induce maximal PROD activity at doses up to 500 mg/kg, and only Aroclor 1016 induced > a half-maximal response at the 500 mg/kg dose. The relative potencies of eighteen different PCB congeners were also determined, and the structures of these compounds differed with respect to the degree of chlorination (tri- to octochloro) and substitution patterns. The relative potencies of these compounds were estimated by comparing their induced activities at the high dose (150 or 100 mg/kg) with that of PB. The most potent inducers were 2,3,3',4',5,6-hexaCB and 2,2',3,4',5,5',6-heptaCB; at a dose of 150 mg/kg, the PROD activity induced by 2,2'3,4',5,5',6-heptaCB was comparable to that observed for PB. 2,3,3',4',5,6-HexaCB was the most potent inducer, and hepatic PROD activity in rats treated with 150 mg/kg was 4202 pmol/min/mg; this value was higher than that observed for PB at a dose of 75 mg/kg. A second group of congeners including 2,2',3,4,4',5,5'-heptaCB, 2,2',4,4',5,5'-hexaCB, 2,2',3,3',4,4',5,5'-octaCB 2,2',4,4'-tetraCB, 2,2',4,5,5'-pentaCB, 2,2',3,4,4',5',6-heptaCB, 2,2',4,4',5-pentaCB and 2,2',3,3',4',5,5',6-octaCB induced PROD activity > or = 1090 pmol/min/mg at the 150 mg/kg dose, and this value was > 50% of the maximal response observed for PB. The remaining compounds, namely 2,4,4'-triCB, 2,2',3,4'-tetraCB, 2,2',5,5'-tetraCB, 2,3',4,4',5-pentaCB, 2,3,3',4,4'-pentaCB, 2,2',4,4',5,6'-hexaCB, 2,3,3',4,4',5,5'-heptaCB and 2,2',3,3',4,4,5-heptaCB were all relatively weak inducers of hepatic microsomal PROD activity ( < 450 pmol/min/mg). In parallel experiments, western blot analysis of immunoreactive CYP2B1 and CYP2B2 protein showed that PB, the PCB mixtures, and congeners induced both proteins. Previous studies have identified a cis-acting DNA element that plays a role in regulating CYP2B1/B2 gene expression and binds nuclear trans-acting factor(s) induced by PB. The results of gel electrophoretic mobility shift assays with nuclear extracts showed that both PB and 2,2',3,4',5,5',6-heptaCB induce formation of a common retarded band using a 32P-labeled oligonucleotide corresponding the the cis-acting DNA promoter sequence. Both PB and PCBs appear to induce CYP2B1/B2 via a common mechanism. Although the results of this study do not define structure-induction (CYP2B1/B2) relationships for PCBs, two compounds, namely 2,3,3',4',5,6-hexaCB and 2,2',3,4',5,5',6-heptaCB, were identified as highly potent inducers.

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
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
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
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
D001140	Aroclors	Industrial chemicals which have become widespread environmental pollutants. Each aroclor is a mixture of chlorinated biphenyls (1200 series) or chlorinated terphenyls (5400 series) or a combination of both (4400 series).	Aroclor
D001483	Base Sequence	The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.	DNA Sequence,Nucleotide Sequence,RNA Sequence,DNA Sequences,Base Sequences,Nucleotide Sequences,RNA Sequences,Sequence, Base,Sequence, DNA,Sequence, Nucleotide,Sequence, RNA,Sequences, Base,Sequences, DNA,Sequences, Nucleotide,Sequences, RNA
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships