Cytochrome P-450 dependent metabolism and mutagenicity of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and their implications in its carcinogenicity

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

Research output: Contribution to journalArticle

Abstract

Methylation of the non-carcinogen 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) at the bay region to form 11-CH3-CPP-17-one confers carcinogenic potential. In the present study we have investigated the in vitro metabolism and mutagenicity of the methylated compound by hepatic microsomal preparations from rats pretreated with various prototype inducers of cytochrome P450 proteins in order to provide a rationale for this marked difference in carcinogenic activity. The most effective metabolism of 11-CH3-CPP-17-one occurred in the presence of Aroclor 1254-induced microsomes, the principal metabolites being oxidative products of the A- and D-rings and of the methyl substituent. When benzo[a]pyrene-induced microsomes served as the metabolising system, the major A-ring metabolite was the 3,4-diol. A similar metabolic pattern was seen with microsomes from rats treated with 11-CH3-CPP-one itself, but the overall effect of metabolism was lower than that observed with benzo[a]pyrene-treated microsomes but higher than that of control animals. In contrast, microsomes from rats treated with clofibrate, dexamethasone, isoniazid and phenobarbitone failed to enhance the metabolism of 11-CH3-CPP-17-one when compared with control microsomes and the metabolites reflected primarily oxidation of the D-ring. When 11-CH3-CPP-17-one was employed as a promutagen in the Ames test, a mutagenic response was evident only in the presence of microsomes from benzo[a]pyrene-induced rats, but induction with phenobarbitone, isoniazid, dexamethasone, clofibrate and the compound itself, failed to elicit a positive mutagenic response. When 3,4-dihydroxy-11-CH3-CPP-17-one served as the promutagen, a mutagenic response was observed in the presence of benzo[a]pyrene-induced and, to a lesser extent, 11-CH3-CPP-17-one-induced microsomes. Treatment of rats with 11-CH3-CPP-17-one caused a marked increase in the O-deethylation of ethoxyresorufin and, to a much lesser extent in epoxide hydrolase activity. It is concluded that (i) 11-CH3CPP-17-one is an inducer of the CYP1 family; (ii) under the present experimental conditions only the CYP1 family can oxidise the A-ring to form the 3,4-dihydroxy-11-CH3-CPP-17-one, the precursor of the ultimate carcinogen and (iii) only the CYP1 family oxidises the diol to generate the ultimate carcinogen. Finally, the carcinogenic potential of the 11-methylated CPP-17-one, when compared with the inactive unsubstituted compound, may be attributed, at least partly, to (1) higher CYP1-catalysed metabolism of the 11-methylated compound to the 3,4-dihydrodiol and (2) more potent induction of the CYP1 family by the 11-substituted derivative, when compared to the parent, unsubstituted compound.
Original languageEnglish
Pages (from-to)1783-1788
JournalCarcinogenesis
Volume14
Issue number9
DOIs
Publication statusPublished - Sep 1993
Externally publishedYes

Fingerprint

Carcinogens
Cytochrome P-450 Enzyme System
Microsomes
Benzo(a)pyrene
Clofibrate
Isoniazid
Phenobarbital
Dexamethasone
15,16-dihydro-11-methylcyclopenta(a)phenanthren-17-one
15,16-dihydrocyclopenta(a)phenanthren-17-one
Chlorodiphenyl (54% Chlorine)
Epoxide Hydrolases
Methylation
Cytochrome P450 Family 1
Liver

Cite this

Boyd, Gary ; Young, Robert J ; Harvey, Ronald G ; Coombs, Maurice M ; Ioannides, Costas. / Cytochrome P-450 dependent metabolism and mutagenicity of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and their implications in its carcinogenicity. In: Carcinogenesis. 1993 ; Vol. 14, No. 9. pp. 1783-1788.
@article{27e3f33cb11b4105b041183dc810512a,
title = "Cytochrome P-450 dependent metabolism and mutagenicity of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and their implications in its carcinogenicity",
abstract = "Methylation of the non-carcinogen 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) at the bay region to form 11-CH3-CPP-17-one confers carcinogenic potential. In the present study we have investigated the in vitro metabolism and mutagenicity of the methylated compound by hepatic microsomal preparations from rats pretreated with various prototype inducers of cytochrome P450 proteins in order to provide a rationale for this marked difference in carcinogenic activity. The most effective metabolism of 11-CH3-CPP-17-one occurred in the presence of Aroclor 1254-induced microsomes, the principal metabolites being oxidative products of the A- and D-rings and of the methyl substituent. When benzo[a]pyrene-induced microsomes served as the metabolising system, the major A-ring metabolite was the 3,4-diol. A similar metabolic pattern was seen with microsomes from rats treated with 11-CH3-CPP-one itself, but the overall effect of metabolism was lower than that observed with benzo[a]pyrene-treated microsomes but higher than that of control animals. In contrast, microsomes from rats treated with clofibrate, dexamethasone, isoniazid and phenobarbitone failed to enhance the metabolism of 11-CH3-CPP-17-one when compared with control microsomes and the metabolites reflected primarily oxidation of the D-ring. When 11-CH3-CPP-17-one was employed as a promutagen in the Ames test, a mutagenic response was evident only in the presence of microsomes from benzo[a]pyrene-induced rats, but induction with phenobarbitone, isoniazid, dexamethasone, clofibrate and the compound itself, failed to elicit a positive mutagenic response. When 3,4-dihydroxy-11-CH3-CPP-17-one served as the promutagen, a mutagenic response was observed in the presence of benzo[a]pyrene-induced and, to a lesser extent, 11-CH3-CPP-17-one-induced microsomes. Treatment of rats with 11-CH3-CPP-17-one caused a marked increase in the O-deethylation of ethoxyresorufin and, to a much lesser extent in epoxide hydrolase activity. It is concluded that (i) 11-CH3CPP-17-one is an inducer of the CYP1 family; (ii) under the present experimental conditions only the CYP1 family can oxidise the A-ring to form the 3,4-dihydroxy-11-CH3-CPP-17-one, the precursor of the ultimate carcinogen and (iii) only the CYP1 family oxidises the diol to generate the ultimate carcinogen. Finally, the carcinogenic potential of the 11-methylated CPP-17-one, when compared with the inactive unsubstituted compound, may be attributed, at least partly, to (1) higher CYP1-catalysed metabolism of the 11-methylated compound to the 3,4-dihydrodiol and (2) more potent induction of the CYP1 family by the 11-substituted derivative, when compared to the parent, unsubstituted compound.",
author = "Gary Boyd and Young, {Robert J} and Harvey, {Ronald G} and Coombs, {Maurice M} and Costas Ioannides",
year = "1993",
month = "9",
doi = "10.1093/carcin/14.9.1783",
language = "English",
volume = "14",
pages = "1783--1788",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "9",

}

Cytochrome P-450 dependent metabolism and mutagenicity of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and their implications in its carcinogenicity. / Boyd, Gary; Young, Robert J; Harvey, Ronald G; Coombs, Maurice M; Ioannides, Costas.

In: Carcinogenesis, Vol. 14, No. 9, 09.1993, p. 1783-1788.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cytochrome P-450 dependent metabolism and mutagenicity of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and their implications in its carcinogenicity

AU - Boyd, Gary

AU - Young, Robert J

AU - Harvey, Ronald G

AU - Coombs, Maurice M

AU - Ioannides, Costas

PY - 1993/9

Y1 - 1993/9

N2 - Methylation of the non-carcinogen 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) at the bay region to form 11-CH3-CPP-17-one confers carcinogenic potential. In the present study we have investigated the in vitro metabolism and mutagenicity of the methylated compound by hepatic microsomal preparations from rats pretreated with various prototype inducers of cytochrome P450 proteins in order to provide a rationale for this marked difference in carcinogenic activity. The most effective metabolism of 11-CH3-CPP-17-one occurred in the presence of Aroclor 1254-induced microsomes, the principal metabolites being oxidative products of the A- and D-rings and of the methyl substituent. When benzo[a]pyrene-induced microsomes served as the metabolising system, the major A-ring metabolite was the 3,4-diol. A similar metabolic pattern was seen with microsomes from rats treated with 11-CH3-CPP-one itself, but the overall effect of metabolism was lower than that observed with benzo[a]pyrene-treated microsomes but higher than that of control animals. In contrast, microsomes from rats treated with clofibrate, dexamethasone, isoniazid and phenobarbitone failed to enhance the metabolism of 11-CH3-CPP-17-one when compared with control microsomes and the metabolites reflected primarily oxidation of the D-ring. When 11-CH3-CPP-17-one was employed as a promutagen in the Ames test, a mutagenic response was evident only in the presence of microsomes from benzo[a]pyrene-induced rats, but induction with phenobarbitone, isoniazid, dexamethasone, clofibrate and the compound itself, failed to elicit a positive mutagenic response. When 3,4-dihydroxy-11-CH3-CPP-17-one served as the promutagen, a mutagenic response was observed in the presence of benzo[a]pyrene-induced and, to a lesser extent, 11-CH3-CPP-17-one-induced microsomes. Treatment of rats with 11-CH3-CPP-17-one caused a marked increase in the O-deethylation of ethoxyresorufin and, to a much lesser extent in epoxide hydrolase activity. It is concluded that (i) 11-CH3CPP-17-one is an inducer of the CYP1 family; (ii) under the present experimental conditions only the CYP1 family can oxidise the A-ring to form the 3,4-dihydroxy-11-CH3-CPP-17-one, the precursor of the ultimate carcinogen and (iii) only the CYP1 family oxidises the diol to generate the ultimate carcinogen. Finally, the carcinogenic potential of the 11-methylated CPP-17-one, when compared with the inactive unsubstituted compound, may be attributed, at least partly, to (1) higher CYP1-catalysed metabolism of the 11-methylated compound to the 3,4-dihydrodiol and (2) more potent induction of the CYP1 family by the 11-substituted derivative, when compared to the parent, unsubstituted compound.

AB - Methylation of the non-carcinogen 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) at the bay region to form 11-CH3-CPP-17-one confers carcinogenic potential. In the present study we have investigated the in vitro metabolism and mutagenicity of the methylated compound by hepatic microsomal preparations from rats pretreated with various prototype inducers of cytochrome P450 proteins in order to provide a rationale for this marked difference in carcinogenic activity. The most effective metabolism of 11-CH3-CPP-17-one occurred in the presence of Aroclor 1254-induced microsomes, the principal metabolites being oxidative products of the A- and D-rings and of the methyl substituent. When benzo[a]pyrene-induced microsomes served as the metabolising system, the major A-ring metabolite was the 3,4-diol. A similar metabolic pattern was seen with microsomes from rats treated with 11-CH3-CPP-one itself, but the overall effect of metabolism was lower than that observed with benzo[a]pyrene-treated microsomes but higher than that of control animals. In contrast, microsomes from rats treated with clofibrate, dexamethasone, isoniazid and phenobarbitone failed to enhance the metabolism of 11-CH3-CPP-17-one when compared with control microsomes and the metabolites reflected primarily oxidation of the D-ring. When 11-CH3-CPP-17-one was employed as a promutagen in the Ames test, a mutagenic response was evident only in the presence of microsomes from benzo[a]pyrene-induced rats, but induction with phenobarbitone, isoniazid, dexamethasone, clofibrate and the compound itself, failed to elicit a positive mutagenic response. When 3,4-dihydroxy-11-CH3-CPP-17-one served as the promutagen, a mutagenic response was observed in the presence of benzo[a]pyrene-induced and, to a lesser extent, 11-CH3-CPP-17-one-induced microsomes. Treatment of rats with 11-CH3-CPP-17-one caused a marked increase in the O-deethylation of ethoxyresorufin and, to a much lesser extent in epoxide hydrolase activity. It is concluded that (i) 11-CH3CPP-17-one is an inducer of the CYP1 family; (ii) under the present experimental conditions only the CYP1 family can oxidise the A-ring to form the 3,4-dihydroxy-11-CH3-CPP-17-one, the precursor of the ultimate carcinogen and (iii) only the CYP1 family oxidises the diol to generate the ultimate carcinogen. Finally, the carcinogenic potential of the 11-methylated CPP-17-one, when compared with the inactive unsubstituted compound, may be attributed, at least partly, to (1) higher CYP1-catalysed metabolism of the 11-methylated compound to the 3,4-dihydrodiol and (2) more potent induction of the CYP1 family by the 11-substituted derivative, when compared to the parent, unsubstituted compound.

U2 - 10.1093/carcin/14.9.1783

DO - 10.1093/carcin/14.9.1783

M3 - Article

VL - 14

SP - 1783

EP - 1788

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 9

ER -