Activation of Some Drug Metabolising Enzymes.

Benford, Diane J. (1980) Activation of Some Drug Metabolising Enzymes. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

Biphenyl 2-hydroxylation was rapidly activated in rat liver microsomes by addition of glucocorticoids or anaphtho-flavone whereas 3- and 4-hydroxylation were unaffected. Betamethasone was the most effective activator. Betamethasone and anaphthoflavone also activated benzo(a)-pyrene 3-hydroxylation and antipyrine 4-hydroxylation. The inter-relationship between these activating agents and the susceptible enzyme activities has been investigated, showing many similarities and some differences. Activation of biphenyl 2-hydroxylation by betamethasone appeared to be unrelated to activation of aromatic amines and UDP-glucuronyltransferases. Activation was not affected by pretreatment of rats with inducing agents but was abolished by addition of the inhibitor metyrapone to microsomal incubations.A marked and most unusual sex difference in activation was found. Activation did not occur in liver microsomes from adult female rats whereas activation in microsomes from immature female rats resembled that from immature male rats. Activation in extrahepatic tissues has also been investigated. An attempt has been made to elucidate the mechanism of activation. There appears to be a direct effect on a cytochrome P-450 dependent enzyme(s), not mediated via the surrounding membrane or the associated reductases. It is suggested that multiple enzymes may be involved in biphenyl 2-hydroxylation and benzo(a)pyrene 3-hydroxylation and that betamethasone and anaphthoflavone may aliosterically activate one or more of these forms. Activation also occurred in human liver microsomes, in isolated rat hepatocytes and in liver microsomes following pretreatment of rats with betamethasone. An important physiological role is proposed for activation by glucocorticoids allowing rapid regulation of enzyme activities before the longer term control, induction, can occur.

Item Type:	Thesis (Doctoral)
Divisions :	Theses
Authors :	Benford, Diane J.
Date :	1980
Additional Information :	Thesis (Ph.D.)--University of Surrey (United Kingdom), 1980.
Depositing User :	EPrints Services
Date Deposited :	24 Apr 2020 15:27
Last Modified :	24 Apr 2020 15:27
URI:	http://epubs.surrey.ac.uk/id/eprint/854864

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