Induction of drug metabolism enzymes by dihalogenated biphenyls.
The effects of pretreatment with symmetrically dihalogenated biphenyls (DXBs, X-F, Cl(C), Br(B) and I) on rat liver drug metabolism enzymes were investigated. 4,4'-DFB, -DCB, and -DBB as well as 2,2'-DFB appeared to be inducers of microsomal cytochrome P-450-linked monoxygenases (N-demethylases of aminopyrine and ethylmorphine). However, no structure-induction relationship was found. 4,4'-DXBs also induced a cytochrome P-448-linked mono-oxygenase (ethoxyresorufin O-deethylase), and their order of induction potential seemed to parallel the increase of the size of the halogen substituent. Therefore, 4,4'-DXB's may be categorized as mixed-type inducers, the cytochrome P-450 component being the more pronounced. Data on the cytochrome P-448 induction by dihalogenated biphenyls with only para substituents may be considered as a refinement of the previously described structure-activity relationship in this respect. All of the DXBs except 3,3'-DCB and 4,4'-DIB, enhanced, like phenobarbital, the activity of UDP-glucuronyltransferase toward 4-hydroxybiphenyl. Only 4,4'-DFB was able to induce the activity of glutathione S-transferase toward 1,2-epoxy-3-(p-nitrophenoxy)propane. Studies after 4,4'-DBB-treatment revealed, like phenobarbital, a preferential induction of ethylmorphine N-demethylase on rough endoplasmic reticulum-derived microsomes, whereas UDP-glucuronyltransferase activity toward 4-hydroxybiphenyl was induced to a larger extent on smooth endoplasmic reticulum microsomes, suggesting a dissimilar enzyme induction in microsomal subfractions.
van Bree
L
L
Department of Medicinal Chemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Commandeur
J
J
Lamberts
B
B
Cornelissen
M
M
van Roon
M
M
Laterveer
H
H
de Vries
J
J
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D008099:Liver / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism; D010105:Oxygenases / Q000096:biosynthesis / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001713:Biphenyl Compounds; D006846:Hydrocarbons, Halogenated; C065775:4,4'-diiodobiphenyl; C065773:4,4'-difluorobiphenyl; D003577:Cytochrome P-450 Enzyme System; C065774:4,4'-dibromobiphenyl; D011078:Polychlorinated Biphenyls; C029861:4,4'-dichlorobiphenyl; D006899:Mixed Function Oxygenases; D010105:Oxygenases; C027270:cytochrome P448-dependent mono-oxygenase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase