The influence of dihydrodiol conformation on the metabolic activation of cyclopenta[a]phenanthrenes.
The present study was undertaken in order to rationalise the apparent biological inactivity of 15,16-dihydro-6-methylcyclopenta[a]phenanthren-17- one (4) when other methyl isomers of 15,16-dihydrocyclopenta[a]phenanthren- -17-one, e.g. the 11-methyl derivative (2), display appreciable tumorigenicity. In vitro metabolism of the 6-methyl-ketone-17-one (4) demonstrated that its principal metabolite was the 3,4-dihydro-3,4-diol (3,4-dihydroxy-6-methyl-3,4,15,16- tetrahydrocyclopenta[a]phenanthren-17-one) (5) which, in the case of the active 11-methyl derivative, is the proximate genotoxin. Thus the inactivity of this 6-methyl-17-ketone cannot be ascribed to lack of formation of the 3,4-dihydro-3,4-diol, the precursor of the 3,4-diol-1,2-epoxides (the ultimate mutagens in this series). However, the 6-methyl-3,4-dihydro-3,4-diol exists in a pseudo-diaxial rather than a pseudo-diequatorial conformation characteristic of the 3,4-dihydro-3,4-diols of the other members of the series. It is therefore suggested that a diequatorial conformation in the dihydrodiol is essential to the metabolic activation of the cyclopenta[a]phenanthren-17-ones.
Boyd
G W
GW
Division of Toxicology, School of Biological Sciences, Guildford, Surrey, UK.
Ioannides
C
C
Coombs
M M
MM
D000818:Animals; D001711:Biotransformation; D006067:Gonanes / Q000378:metabolism* / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
C092135:15,16-dihydro-6-methylcyclopenta(a)phenanthren-17-one; D006067:Gonanes; D009153:Mutagens