Induction of drug metabolism enzymes by dihalogenated biphenyls

✍ Scribed by van Bree, L. ;Commandeur, J. ;Lamberts, B. ;Cornelissen, M. ;van Roon, M. ;Laterveer, H. ;de Vries, J.

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: English
• Weight: 700 KB
• Volume: 5
• Category: Article
• ISSN: 0887-2082
• DOI: 10.1002/jbt.2570050109

✦ Synopsis

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 0-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 4hydroxybiphenyl. Only 4,4'-DFB was able to induce the activity of glutathione S-transferase toward 1,2epoxy-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 4hydroxybiphenyl was induced to a larger extent on smooth endoplasmic reticulum microsomes, suggesting a dissimilar enzyme induction in microsomal subfractions.