CYP1 induction, binding to the hepatic aromatic hydrocarbon receptor and mutagenicity of a series of 11-alkoxy cyclopenta[a]phenanthren-17-ones: a structure activity relationship.
A series of four 11-alkoxy cyclopenta[a]phenanthren-17-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.
Boyd
G W
GW
Molecular Toxicology Group, School of Biological Sciences, Guildford, Surrey, UK.
Coombs
M M
MM
Ioannides
C
C
D000818:Animals; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006067:Gonanes / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000633:toxicity*; D011083:Polycyclic Compounds / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012475:Salmonella / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D006067:Gonanes; D009153:Mutagens; D010616:Phenanthrenes; D011083:Polycyclic Compounds; C011770:15,16-dihydrocyclopenta(a)phenanthren-17-one; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2