The influence of dihydrodiol formation on the metabolic activation of the cyclopenta[a]phenanthrenes

Gary Boyd, Costas Ioannides, Maurice M Coombs

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Abstract

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-rmdiol (3,4-dihydroxy-6-methyl-3,4,15,16- tetrahydrocyclopenta[a]phenanthren-17-one) (5) which, is 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-l,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.
Original languageEnglish
Pages (from-to)93-100
JournalToxicology Letters
Volume75
Issue number1-3
DOIs
Publication statusPublished - Jan 1995
Externally publishedYes

Keywords

  • Cytochromes P450
  • Polycyclic aromatic hydrocarbons
  • Cyclopenta[a]phenanthrenes

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