Prasad G K, Thakker D R
Laboratory of Molecular Pharmacology, Food and Drug Administration, Bethesda, Maryland 20892.
Biochem Biophys Res Commun. 1991 Dec 31;181(3):1516-23. doi: 10.1016/0006-291x(91)92111-v.
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.
我们之前已经表明，经3-甲基胆蒽处理的大鼠肝脏微粒体对致癌性6-氟苯并[c]菲的代谢产生K-区域氧化物作为主要代谢产物，而在相同条件下苯并[c]菲的代谢过程中没有K-区域氧化物留存。为了解氟基团对该烃类化合物生成K-区域氧化物的影响，我们测定了代谢产物6-氟苯并[c]菲-7,8-氧化物的对映体组成和绝对构型。有趣的是，微粒体细胞色素P-450c从苯并[c]菲主要形成5R,6S对映体，而它对6-氟苯并[c]菲的立体选择性则相反，主要形成7S,8R对映体。我们将这一观察结果归因于氟基团与该同工酶疏水结合口袋之间的不利相互作用。
