The metabolism and activation of 15,16-dihydrocyclopenta[a]phenanthren-17-one by cytochrome P-450 proteins

Gary Boyd, Robert J Young, Ronald G Harvey, Maurice M Coombs, Costas Ioannides

Research output: Contribution to journalArticle

Abstract

The in vitro metabolism and activation to mutagens of 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) were investigated using hepatic preparations from rats pretreated with prototype inducers of the cytochrome P-450-dependent mixed-function oxidases. Aroclor 1254-induced microsomes were the most effective metabolisers of this compound, the major metabolites being oxidation products of the bay region A ring. To a lesser extent hydroxylation of the non-aromatic D ring occurred, the products being the 15- and 16-hydroxyderivatives. Oxidation of the A ring was also achieved with microsomes from benzo[a]pyrene-treated rats but not with those from rats treated with clofibrate, phenobarbitone, isoniazid, dexamethasone and CPP-17-one itself, where the metabolites were primarily the oxidation products of the D ring. When CPP-17-one was used as a promutagen in the Ames test, only microsomes from Aroclor 1254-treated rats could elicit a positive mutagenic response. When 3,4-dihydrodihydroxy-CPP-17-one, the precursor of the ultimate mutagen, was used as the promutagen, a positive response was observed with microsomes from Aroclor 1254- and benzo[a]pyrene-treated rats. It is concluded that (a) CPP-17-one is metabolised through oxidation of the D ring to produce non-mutagenic products and only through A ring oxidation mutagens are produced, (b) only the CYP1A (cytochrome P-450 family 1, subfamily A) family (induced by benzo[a]pyrene and Aroclor 1254) could oxidise the A ring, and (c) Aroclor 1254-induced hepatic microsomes are the most effective catalysts of the metabolism and activation of CPP-17-one because, in addition to the high CYP1A activity, they are also characterised by high levels of microsomal epoxide hydrolase.
Original languageEnglish
Pages (from-to)275-282
JournalEuropean Journal of Pharmacology
Volume228
Issue number5-6
DOIs
Publication statusPublished - 1993
Externally publishedYes

Fingerprint

Chlorodiphenyl (54% Chlorine)
Metabolism
Cytochrome P-450 Enzyme System
Rats
Mutagens
Chemical activation
Microsomes
Proteins
Pyrene
Oxidation
Benzo(a)pyrene
Metabolites
Hydrolases
Hydroxylation
Epoxide Hydrolases
Clofibrate
Liver
Isoniazid
Phenobarbital
Mixed Function Oxygenases

Cite this

Boyd, Gary ; Young, Robert J ; Harvey, Ronald G ; Coombs, Maurice M ; Ioannides, Costas. / The metabolism and activation of 15,16-dihydrocyclopenta[a]phenanthren-17-one by cytochrome P-450 proteins. In: European Journal of Pharmacology. 1993 ; Vol. 228, No. 5-6. pp. 275-282.
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abstract = "The in vitro metabolism and activation to mutagens of 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) were investigated using hepatic preparations from rats pretreated with prototype inducers of the cytochrome P-450-dependent mixed-function oxidases. Aroclor 1254-induced microsomes were the most effective metabolisers of this compound, the major metabolites being oxidation products of the bay region A ring. To a lesser extent hydroxylation of the non-aromatic D ring occurred, the products being the 15- and 16-hydroxyderivatives. Oxidation of the A ring was also achieved with microsomes from benzo[a]pyrene-treated rats but not with those from rats treated with clofibrate, phenobarbitone, isoniazid, dexamethasone and CPP-17-one itself, where the metabolites were primarily the oxidation products of the D ring. When CPP-17-one was used as a promutagen in the Ames test, only microsomes from Aroclor 1254-treated rats could elicit a positive mutagenic response. When 3,4-dihydrodihydroxy-CPP-17-one, the precursor of the ultimate mutagen, was used as the promutagen, a positive response was observed with microsomes from Aroclor 1254- and benzo[a]pyrene-treated rats. It is concluded that (a) CPP-17-one is metabolised through oxidation of the D ring to produce non-mutagenic products and only through A ring oxidation mutagens are produced, (b) only the CYP1A (cytochrome P-450 family 1, subfamily A) family (induced by benzo[a]pyrene and Aroclor 1254) could oxidise the A ring, and (c) Aroclor 1254-induced hepatic microsomes are the most effective catalysts of the metabolism and activation of CPP-17-one because, in addition to the high CYP1A activity, they are also characterised by high levels of microsomal epoxide hydrolase.",
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The metabolism and activation of 15,16-dihydrocyclopenta[a]phenanthren-17-one by cytochrome P-450 proteins. / Boyd, Gary; Young, Robert J; Harvey, Ronald G; Coombs, Maurice M; Ioannides, Costas.

In: European Journal of Pharmacology, Vol. 228, No. 5-6, 1993, p. 275-282.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The metabolism and activation of 15,16-dihydrocyclopenta[a]phenanthren-17-one by cytochrome P-450 proteins

AU - Boyd, Gary

AU - Young, Robert J

AU - Harvey, Ronald G

AU - Coombs, Maurice M

AU - Ioannides, Costas

PY - 1993

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AB - The in vitro metabolism and activation to mutagens of 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) were investigated using hepatic preparations from rats pretreated with prototype inducers of the cytochrome P-450-dependent mixed-function oxidases. Aroclor 1254-induced microsomes were the most effective metabolisers of this compound, the major metabolites being oxidation products of the bay region A ring. To a lesser extent hydroxylation of the non-aromatic D ring occurred, the products being the 15- and 16-hydroxyderivatives. Oxidation of the A ring was also achieved with microsomes from benzo[a]pyrene-treated rats but not with those from rats treated with clofibrate, phenobarbitone, isoniazid, dexamethasone and CPP-17-one itself, where the metabolites were primarily the oxidation products of the D ring. When CPP-17-one was used as a promutagen in the Ames test, only microsomes from Aroclor 1254-treated rats could elicit a positive mutagenic response. When 3,4-dihydrodihydroxy-CPP-17-one, the precursor of the ultimate mutagen, was used as the promutagen, a positive response was observed with microsomes from Aroclor 1254- and benzo[a]pyrene-treated rats. It is concluded that (a) CPP-17-one is metabolised through oxidation of the D ring to produce non-mutagenic products and only through A ring oxidation mutagens are produced, (b) only the CYP1A (cytochrome P-450 family 1, subfamily A) family (induced by benzo[a]pyrene and Aroclor 1254) could oxidise the A ring, and (c) Aroclor 1254-induced hepatic microsomes are the most effective catalysts of the metabolism and activation of CPP-17-one because, in addition to the high CYP1A activity, they are also characterised by high levels of microsomal epoxide hydrolase.

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DO - 10.1016/0926-6917(93)90061-T

M3 - Article

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