Cytochrome P-450-mediated metabolism of biphenyl and the 4-halobiphenyls
Identifieur interne : 005133 ( Main/Exploration ); précédent : 005132; suivant : 005134Cytochrome P-450-mediated metabolism of biphenyl and the 4-halobiphenyls
Auteurs : Andrew Parkinson [Canada] ; Stephen Safe [Canada]Source :
- Biochemical Pharmacology [ 0006-2952 ] ; 1982.
Abstract
The in vitro metabolism of biphenyl, 4-fluoro-, 4-chloro-, 4-bromo- and 4-iodobiphenyl by cytochrome P-450-dependent monooxygenases was investigated using hepatic microsomes from immature male rats pretreated with phenobarbitonc or 3-methylcholanthrene. The major route of metabolism of biphenyl and the 4-halobiphenyls was 4'-hydroxylation. i.e. para to the phenyl-phenyl bridge. The minor route of metabolism apparently changed from 2-hydroxylation for biphenyl (i.e. ortho to the phenyl-phenyl bridge) to 3-hydroxylation for all 4-halobiphenyls (i.e. ortho to the halogen). In marked contrast to biphenyl, the regioselectivity of 4-halobiphenyl metabolism was not altered by pretreatment of rats with either phenobarbitone or 3-methylcholanthrene. The overall rate of metabolism of 4-fluoro- and 4-bromobiphenyl to water-soluble metabolites increased 2-fold and 5- to 6-fold using microsomes from rats pretreated with phenobarbitone and 3-methylcholanthrene respectively. In contrast, the overall rates of metabolism of 4-chloro- and 4-iodobiphenyl were refractory to the inductive effects of phenobarbitone but were increased more than 10-fold following pretreatment with 3-methylcholanthrene. There was a correlation between the apparent binding affinities of microsomes from phenobarbitone-treated rats for biphenyl and the 4-halobiphenyls and their calculated log octanol/water partition coefficients (lipophilicity). However, the effects of the halogen substituents on the rates of metabolism of the 4-halobiphenyls by microsomes from control and induced rats did not correlate with their binding affinities or with any physiochemical differences between the fluoro, chloro, bromo and iodo substituents.
Url:
DOI: 10.1016/0006-2952(82)90487-7
Affiliations:
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The major route of metabolism of biphenyl and the 4-halobiphenyls was 4'-hydroxylation. i.e. para to the phenyl-phenyl bridge. The minor route of metabolism apparently changed from 2-hydroxylation for biphenyl (i.e. ortho to the phenyl-phenyl bridge) to 3-hydroxylation for all 4-halobiphenyls (i.e. ortho to the halogen). In marked contrast to biphenyl, the regioselectivity of 4-halobiphenyl metabolism was not altered by pretreatment of rats with either phenobarbitone or 3-methylcholanthrene. The overall rate of metabolism of 4-fluoro- and 4-bromobiphenyl to water-soluble metabolites increased 2-fold and 5- to 6-fold using microsomes from rats pretreated with phenobarbitone and 3-methylcholanthrene respectively. In contrast, the overall rates of metabolism of 4-chloro- and 4-iodobiphenyl were refractory to the inductive effects of phenobarbitone but were increased more than 10-fold following pretreatment with 3-methylcholanthrene. There was a correlation between the apparent binding affinities of microsomes from phenobarbitone-treated rats for biphenyl and the 4-halobiphenyls and their calculated log octanol/water partition coefficients (lipophilicity). However, the effects of the halogen substituents on the rates of metabolism of the 4-halobiphenyls by microsomes from control and induced rats did not correlate with their binding affinities or with any physiochemical differences between the fluoro, chloro, bromo and iodo substituents.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Parkinson, Andrew" sort="Parkinson, Andrew" uniqKey="Parkinson A" first="Andrew" last="Parkinson">Andrew Parkinson</name></noRegion><name sortKey="Safe, Stephen" sort="Safe, Stephen" uniqKey="Safe S" first="Stephen" last="Safe">Stephen Safe</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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