CYP1 induction, binding to the hepatic aromatic hydrocarbon receptor and the mutagenicity of a series of 11-alkoxy-cyclopenta[a]phenthren-17-ones: a structure/activity relationship

Gary Boyd, Maurice M Coombs, Costas Ioannides

Research output: Contribution to journalArticle

Abstract

A series of four 11-alkoxy cyclopenta[a]phenanthren-l7-ones, ranging from the methoxy to the butoxy derivative, has been synthesised in order to investigate the effect of the size of the 11-substituent on the mutagenicity and ability of these compounds to induce hepatic CYP1 activity in rats. The latter was monitored by using as diagnostic probes methoxy and ethoxy-resorufin, and immunologically in Western blots employing anti-CYP1A1 antibodies. All four members of the series induced both CYP1A1 and CYP1A2 activities and apoprotein levels, but the methoxy- and ethoxy-CPP-17-ones were clearly the most potent. Of the four isomers, only 11-methoxy-CPP-17-one displaced 3H-TCDD from the cytosolic Ah receptor. Similarly only 11-methoxy-CPP-17-one elicited a positive mutagenic response in the Ames test in the presence of an Aroclor 1254-induced activation system. The relevance of these findings to the carcinogenicity of these compounds in the mouse skin painting model is discussed.
Original languageEnglish
Pages (from-to)27-35
JournalToxicology
Volume95
Issue number1-3
DOIs
Publication statusPublished - Jan 1995
Externally publishedYes

Fingerprint

Aromatic Hydrocarbons
Cytochrome P-450 CYP1A1
Chlorodiphenyl (54% Chlorine)
Cytochrome P-450 CYP1A2
Apoproteins
Painting
Isomers
Rats
Skin
Chemical activation
Derivatives
Antibodies
15,16-dihydrocyclopenta(a)phenanthren-17-one
alkoxyl radical

Keywords

  • Polycyclic aromatic hydrocarbons
  • Cyclopenta[a]phenanthrenes
  • Cytochrome P-450
  • Ah receptor
  • Enzyme induction

Cite this

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title = "CYP1 induction, binding to the hepatic aromatic hydrocarbon receptor and the mutagenicity of a series of 11-alkoxy-cyclopenta[a]phenthren-17-ones: a structure/activity relationship",
abstract = "A series of four 11-alkoxy cyclopenta[a]phenanthren-l7-ones, ranging from the methoxy to the butoxy derivative, has been synthesised in order to investigate the effect of the size of the 11-substituent on the mutagenicity and ability of these compounds to induce hepatic CYP1 activity in rats. The latter was monitored by using as diagnostic probes methoxy and ethoxy-resorufin, and immunologically in Western blots employing anti-CYP1A1 antibodies. All four members of the series induced both CYP1A1 and CYP1A2 activities and apoprotein levels, but the methoxy- and ethoxy-CPP-17-ones were clearly the most potent. Of the four isomers, only 11-methoxy-CPP-17-one displaced 3H-TCDD from the cytosolic Ah receptor. Similarly only 11-methoxy-CPP-17-one elicited a positive mutagenic response in the Ames test in the presence of an Aroclor 1254-induced activation system. The relevance of these findings to the carcinogenicity of these compounds in the mouse skin painting model is discussed.",
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CYP1 induction, binding to the hepatic aromatic hydrocarbon receptor and the mutagenicity of a series of 11-alkoxy-cyclopenta[a]phenthren-17-ones : a structure/activity relationship. / Boyd, Gary; Coombs, Maurice M; Ioannides, Costas.

In: Toxicology, Vol. 95, No. 1-3, 01.1995, p. 27-35.

Research output: Contribution to journalArticle

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AB - A series of four 11-alkoxy cyclopenta[a]phenanthren-l7-ones, ranging from the methoxy to the butoxy derivative, has been synthesised in order to investigate the effect of the size of the 11-substituent on the mutagenicity and ability of these compounds to induce hepatic CYP1 activity in rats. The latter was monitored by using as diagnostic probes methoxy and ethoxy-resorufin, and immunologically in Western blots employing anti-CYP1A1 antibodies. All four members of the series induced both CYP1A1 and CYP1A2 activities and apoprotein levels, but the methoxy- and ethoxy-CPP-17-ones were clearly the most potent. Of the four isomers, only 11-methoxy-CPP-17-one displaced 3H-TCDD from the cytosolic Ah receptor. Similarly only 11-methoxy-CPP-17-one elicited a positive mutagenic response in the Ames test in the presence of an Aroclor 1254-induced activation system. The relevance of these findings to the carcinogenicity of these compounds in the mouse skin painting model is discussed.

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