Oxidative conversion of 6-fluorobenzo(c)phenanthrene to its K-region oxide by liver microsomes from 3-methylcholanthrene treated rats: reversal of stereoselectivity of cytochrome P-450c due to the influence of fluoro group.
We have shown earlier that metabolism of carcinogenic 6-fluorobenzo(c)-phenanthrene by liver microsomes of 3-methylcholanthrene treated rats generate K-region oxide as the major metabolite, while no K-region oxide survives in benzo(c)-phenanthrene metabolism under identical conditions. To understand the influence of fluoro group on the generation of K-region oxide from this hydrocarbon, we have determined the enantiomeric composition and absolute configuration of the metabolic 6-fluorobenzo(c)phen-anthrene-7,8-oxide. Interestingly, the microsomal cytochrome P-450c forms predominantly the 5R,6S enantiomer from B(c)Ph, while it exhibits a reversal of stereoselectivity with 6-fluorobenzo(c)phenanthrene forming predominantly the 7S,8R enantiomer. We have attributed this observation to an unfavourable interaction of the fluoro group with the hydrophobic binding pocket of the isozyme.
Prasad
G K
GK
Laboratory of Molecular Pharmacology, Food and Drug Administration, Bethesda, Maryland 20892.
Thakker
D R
DR
D000818:Animals; D001665:Binding Sites; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism*; D007536:Isomerism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010616:Phenanthrenes / Q000378:metabolism*; D051381:Rats
D002273:Carcinogens; D006845:Hydrocarbons, Fluorinated; D010616:Phenanthrenes; C055179:6-fluorobenzo(c)phenanthrene; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System